Abstract

Objective

To evaluate the incidence and clinical significance of retropharyngeal lymph node metastasis in hypopharyngeal cancer.

Methods

Pretreatment computed tomography and/or magnetic resonance images of 152 patients treated between 1998 and 2009 were retrospectively reviewed. The prognostic significance of retropharyngeal lymph node metastasis for 116 patients who received definitive treatment was also analyzed.

Results

Twelve patients (8%) were radiologically positive for retropharyngeal lymph node metastasis. Tumors originating from the posterior wall showed significantly higher incidence of retropharyngeal lymph node than those originating from other sites (23.8 vs. 5.3%, P = 0.01). The majority of patients with retropharyngeal lymph node involvement experienced distant metastasis. The overall survival rate of patients with retropharyngeal lymph node metastasis was worse than in those lacking retropharyngeal lymph node involvement (0 vs. 68.8% at 2 years, P < 0.01), and so was the cause-specific survival rate (0 vs. 74% at 2 years, P < 0.01).

Conclusions

Patients with hypopharyngeal cancer, especially those with posterior wall tumors, are at high risk for retropharyngeal lymph node involvement. Patients with retropharyngeal lymph node metastasis developed distant metastasis frequently, and showed dismal outcomes.

INTRODUCTION

Retropharyngeal lymph node (RPLN) metastases have been reported from cancers of almost all sites of the head and neck (1). The incidence and clinical significance of RPLN involvement have been widely examined in patients with nasopharyngeal cancer (2,3). As for primary tumors other than nasopharyngeal cancer, Hasegawa and Matsuura (4) reported their experience with RPLN dissection in patients with oro- and hypopharyngeal cancers, revealing that 50% of patients harbored metastasis. Several institutions reported the effectiveness of radiological examination such as computed tomography (CT) or magnetic resonance imaging (MRI) for clinical diagnosis of RPLN. Among 42 patients with oro- and hypopharyngeal carcinomas who underwent RPLN dissection, radiological examination preoperatively identified five in six patients having metastatic foci in their RPLNs (5). Authors in that study concluded that radiological diagnosis CT or MRI is very useful and effective for metastasis diagnosis of RPLN metastasis.

In patients with hypopharyngeal cancer, two Japanese groups reported in their surgical series that 14.8–18% of patients had pathologically positive RPLNs (6,7). More recently, another Japanese group reported that metastasis to RPLNs, evaluated radiologically or pathologically, occurred in 13.2% of patients during their follow-up period (8). However, there has been no published report evaluating the incidence of RPLN involvement solely by radiological examinations. Furthermore, the clinical significance of RPLN involvement in hypopharyngeal cancer has yet to be determined. Thus, we have evaluated the incidence of RPLN metastasis retrospectively and examined its impact on patient survival.

PATIENTS AND METHODS

Patient Population

Incidence of RPLN

We have reviewed the clinical records and radiological studies of 152 patients with squamous carcinoma of the hypopharynx who were referred to our institution between October 1998 and December 2009. Detailed patient characteristics are presented in Table 1. One hundred and thirty-five patients (89%) were male, and the median age of all patients was 66 years ranging from 48 to 95. Primary tumors were located at the piriform sinus (n = 106, 70%), postcricoid area (n = 25, 16%) and posterior wall (n = 21, 14%). For disease staging, patients underwent a historical and physical examination, including direct and/or indirect laryngoscope, and CT of the head and neck, and chest. Patients were also subjected to a barium study of the upper gastrointestinal tract or esophagogastroduodenoscopy to rule out the presence of esophageal cancer. Staging was determined according to the UICC TNM classification system (1997). More than half of the patients (n = 86, 57%) had locally advanced disease (T3 and 4), and 118 patients (78%) presented with lymph node metastases.

Table 1.

Patient and tumor characteristics

Characteristics n (%) 
All 152 (100) 
Age 
 Median 66 
 Range 48–95 
Gender 
 Male 135 (89) 
 Female 17 (11) 
Subsite 
 Piriform sinus 106 (70) 
 Postcricoid area 25 (16) 
 Posterior wall 21 (14) 
T-stage 
 T1 16 (11) 
 T2 50 (33) 
 T3 31 (20) 
 T4 55 (36) 
N-stage 
 N0 34 (22) 
 N1 21 (14) 
 N2 86 (57) 
 N3 11 (7) 
Clinical stage 
 Stage I 10 (7) 
 Stage II 12 (8) 
 Stage III 23 (15) 
 Stage IV 107 (70) 
Characteristics n (%) 
All 152 (100) 
Age 
 Median 66 
 Range 48–95 
Gender 
 Male 135 (89) 
 Female 17 (11) 
Subsite 
 Piriform sinus 106 (70) 
 Postcricoid area 25 (16) 
 Posterior wall 21 (14) 
T-stage 
 T1 16 (11) 
 T2 50 (33) 
 T3 31 (20) 
 T4 55 (36) 
N-stage 
 N0 34 (22) 
 N1 21 (14) 
 N2 86 (57) 
 N3 11 (7) 
Clinical stage 
 Stage I 10 (7) 
 Stage II 12 (8) 
 Stage III 23 (15) 
 Stage IV 107 (70) 

Prognostic Evaluation

Among the 152 enrolled patients, 116 patients who received curative treatment at our institution comprised another cohort to evaluate the prognostic significance of RPLN metastasis. We defined curative treatment as therapies with the potential to eradicate the cancer, that is, surgery or radiotherapy with total dose more than 60 Gy. The treatment modality was determined in accordance with the institution's guidelines. As a general rule, patients with advanced primary site disease (cT3–4) are managed with surgery. Patients with more localized disease (cT1–2), who wish to preserve their larynx and who are medically unfit for surgery are primarily treated by radiotherapy. Bulky T4 disease, tumors fixed to the cervical spine and lymphadenopathy encasing carotid arteries are deemed unresectable; eight patients were regarded to have unresectable disease. Of particular note is that no metastatic RPLNs were found in these patients with unresectable disease.

Eighty patients were treated primarily by radiotherapy with or without concomitant chemotherapy. Radiotherapy was delivered by a conventional fractionation schedule (1.8–2.0 Gy per fraction). The total dose was 66–70 Gy to the gross tumor volume, and 45–50 Gy to the prophylactic area above the clavicle. Concomitant chemotherapy consisted of cisplatin 100 mg per body and 5-fluorouracil 5000 mg per body administered continuously for 120 h every 3 weeks. Patients with residual disease after primary treatment underwent salvage surgery.

Thirty-six patients were treated with surgery followed by postoperative radiotherapy with or without concomitant chemotherapy. Surgery consisted of total pharyngectomy and radical neck dissection for patients with lymph node metastases or selected dissection for N0 patients. Postoperative radiotherapy consisted of 60 Gy in 30 daily fractions of 2 Gy followed by an additional boost of 10 Gy if necessary (i.e. extranodal spread of lymph node metastases or positive surgical margins). The chemotherapy regimen in the postoperative setting was the same as that in primary chemoradiotherapy.

Thirty-six patients who did not receive curative treatment at our institution include: 25 patients who received only palliative treatment, mostly because of age, poor performance status and comorbid medical conditions; 8 patients who were treated somewhere else and 3 patients who never showed up for the treatment.

Radiological Studies

Three diagnostic radiologists experienced in head and neck imaging retrospectively evaluated pretreatment CT or MRI. Differences in their assessment were resolved through discussion. RPLN was considered as metastatic when they measured 10 mm or more along their short axis according to the criteria proposed by Mancuso et al. (9,10). Lymph nodes showing central hypodensity on CT or hyperintensity on T2-weighted MRI were also considered metastatic irrespective of their size.

Statistical Methods

Fisher's exact test was used to examine the differences in the incidence of RPLN metastasis between different subgroups. Multivariate analysis was performed using logistic regression analysis.

Survival curves were constructed by the Kaplan–Meier method (11), and the difference was compared using the log-rank test. Overall and cause-specific survival rate were calculated from date to our referral. A P value (two-tailed) <0.05 was considered significant. Multivariate analysis was conducted by using a Cox regression model to assess the independence and significance of each parameter (primary tumor site, T-stage, N-stage, clinical stage, treatment and RPLN involvement).

RESULTS

Incidence of Retropharyngeal Nodes

Sixty-six patients had both CT and MRI available for review, while the other 86 patients had CT alone. Of all 152 patients, 12 were positive for RPLN metastasis (7.9%). All metastatic RPLNs were located ipsilateral to the primary site. Table 2 demonstrates the association between RPLN incidence and several factors. The incidence of RPLN metastasis according to the primary tumor location was 23.8% (n = 5) in the posterior wall, 6.3% (n = 7) in the piriform sinus and 0% in the postcricoid area. Posterior wall tumors had a significantly higher incidence of positive RPLNs compared with the piriform sinus and postcricoid area combined (P = 0.01). Patients with a locally advanced (T3 and 4) tumor had more frequent involvement of RPLNs than those with a localized tumor (11.6 vs. 3.0%, respectively), with marginal significance (P = 0.07). Of the 12 patients with RPLN metastases, 11 had cervical lymph node metastases other than RPLN. However, concerning the rate of RPLN metastasis, the analysis showed no significant difference between the N+ and N0 groups (P = 0.3). Multivariate analysis revealed that only the tumor subsite (posterior wall) significantly predicted RPLN involvement (P < 0.01).

Table 2.

Incidence of positive retropharyngeal lymph nodes (RPLNs) according to clinical factors

  RPLN
 
P value 
Positive (%) Negative (%) 
Subsite 
 PS + PC 7 (5) 124 (95) 0.013 
 PW 5 (24) 16 (76) 
T-stage 
 T1–2 2 (3) 64 (97) 0.07 
 T3–4 10 (12) 76 (88) 
N-stage 
 N0 1 (3) 33 (97) 0.3 
 N1–3 11 (9) 107 (91) 
Clinical stage 
 Stages I–II 0 (0) 22 (100) 0.2 
 Stages III–IV 12 (9) 118 (91) 
  RPLN
 
P value 
Positive (%) Negative (%) 
Subsite 
 PS + PC 7 (5) 124 (95) 0.013 
 PW 5 (24) 16 (76) 
T-stage 
 T1–2 2 (3) 64 (97) 0.07 
 T3–4 10 (12) 76 (88) 
N-stage 
 N0 1 (3) 33 (97) 0.3 
 N1–3 11 (9) 107 (91) 
Clinical stage 
 Stages I–II 0 (0) 22 (100) 0.2 
 Stages III–IV 12 (9) 118 (91) 

PS, piriform sinus; PC, postcricoid area; PW, posterior wall.

Prognostic Evaluation

As mentioned above, an evaluation for prognosis was done only for 116 patients who were curatively treated at our institution. Patient characteristics in each treatment group are shown in Table 3.

Table 3.

Patient characteristics classified by the treatment modality

 RT (%) Surgery (%) 
Number of patients 80 36 
Age (mean) 46–84 (67) 55–81 (66) 
Gender 
 Male 70 (88) 33 (92) 
 Female 10 (12) 3 (8) 
T-stage 
 T1–2 47 (59) 7 (19) 
 T3–4 33 (41) 29 (81) 
N-stage 
 N0 28 (35) 4 (11) 
 N1–3 52 (65) 32 (89) 
Primary site 
 Piriform sinus 51 (63) 32 (89) 
 Postcricoid 15 (19) 3 (8) 
 Posterior wall 14 (18) 1 (3) 
RPLN metastases 
 Positive 4 (5) 4 (11) 
 Negative 76 (95) 32 (89) 
Chemotherapy 
 Yes 55 (69) 14 (39) 
 No 25 (31) 22 (61) 
 RT (%) Surgery (%) 
Number of patients 80 36 
Age (mean) 46–84 (67) 55–81 (66) 
Gender 
 Male 70 (88) 33 (92) 
 Female 10 (12) 3 (8) 
T-stage 
 T1–2 47 (59) 7 (19) 
 T3–4 33 (41) 29 (81) 
N-stage 
 N0 28 (35) 4 (11) 
 N1–3 52 (65) 32 (89) 
Primary site 
 Piriform sinus 51 (63) 32 (89) 
 Postcricoid 15 (19) 3 (8) 
 Posterior wall 14 (18) 1 (3) 
RPLN metastases 
 Positive 4 (5) 4 (11) 
 Negative 76 (95) 32 (89) 
Chemotherapy 
 Yes 55 (69) 14 (39) 
 No 25 (31) 22 (61) 

RT, radiotherapy; RPLN, retropharyngeal lymph node.

Fifty-six patients (70%) in the primary radiotherapy group have completed their planned course of radiation. Among 24 patients who did not, 14 patients could not complete their treatment due to severe acute toxicity. The other 10 patients experienced disease progression half way through radiotherapy, and therefore underwent surgical resection. All 36 patients in the primary surgery group have successfully completed their postoperative radiotherapy.

Eight patients (6.8%) in this cohort were found to have RPLN metastasis. Of the eight patients with RPLN metastasis, four patients were treated primarily by radiotherapy with concomitant chemotherapy in two patients. All metastatic RPLNs were irradiated to 70 Gy. The remaining four patients underwent primary surgery followed by postoperative chemoradiotherapy. Two of these four patients also underwent RPLN dissection at the time of primary surgery.

Of the 116 patients, 20 patients (18%) had loco-regional recurrence. There was no significant difference between individual subgroups in both univariate and multivariate analysis. Only one of the eight patients with RPLN metastasis later presented with regional failure. It is worth noting that RPLN was also involved at the time of this patient's failure.

Distant metastasis developed in 32% of these 116 patients at 5 years. Patients with RPLN metastasis developed more distant metastasis than those without (66.7 vs. 29.7% at 2 years, P < 0.0001). Additionally, we identified a significant correlation with N (P = 0.005) but not T-stage classification (P = 0.29). In multivariate analysis, only RPLN involvement independently predicted distant metastasis [hazards ratio (HR) = 4.09 (95% confidential interval {CI} 1.17–14.31), P = 0.02] (Table 4).

Table 4.

Multivariate analysis of cause-specific survival and the distant metastasis rate

  Cause-specific survival
 
Distant metastasis
 
HR 95% CI P value HR 95% CI P value 
RPLN 
 Positive vs. negative 3.60 1.14–10.66 0.03 7.78 2.69–22.5 <0.001 
Subsite 
 PW vs. PS/PC 1.20 0.37–4.26 0.72 0.54 0.18–1.63 0.28 
T-stage 
 3/4 vs. 1/2 1.60 0.76–3.38 0.22 1.20 0.59–2.44 0.61 
N-stage 
 1–3 vs. 0 3.33 0.77–14.3 0.11 2.39 0.55–10.5 0.94 
Clinical stage 
 III/IV vs. I/II 1.15 0.14–9.43 0.90 0.55 0.09–3.09 0.55 
Treatment 
 RT vs. surgery 0.92 0.45–1.86 0.82 1.86 0.82–4.22 0.13 
  Cause-specific survival
 
Distant metastasis
 
HR 95% CI P value HR 95% CI P value 
RPLN 
 Positive vs. negative 3.60 1.14–10.66 0.03 7.78 2.69–22.5 <0.001 
Subsite 
 PW vs. PS/PC 1.20 0.37–4.26 0.72 0.54 0.18–1.63 0.28 
T-stage 
 3/4 vs. 1/2 1.60 0.76–3.38 0.22 1.20 0.59–2.44 0.61 
N-stage 
 1–3 vs. 0 3.33 0.77–14.3 0.11 2.39 0.55–10.5 0.94 
Clinical stage 
 III/IV vs. I/II 1.15 0.14–9.43 0.90 0.55 0.09–3.09 0.55 
Treatment 
 RT vs. surgery 0.92 0.45–1.86 0.82 1.86 0.82–4.22 0.13 

HR, hazards ratio; CI, confidence interval.

The overall survival rates at 2 and 5 years were 62.4 and 55.7%, respectively (Fig. 1). The survival rate of the radiotherapy group and the surgery group at 2 years were 68.2 and 69.9%, respectively (P = 0.2) (Fig. 2). Patients with RPLN metastasis showed a significantly poorer outcome than those without (0 vs. 68.8% at 2 years, P < 0.01). Additionally, RPLN metastasis was also associated with a poorer cause-specific prognosis (0 vs. 74% at 2 years, P < 0.01). In multivariate analysis, RPLN metastasis alone was significantly and independently associated with cause-specific survival [HR = 3.60 (95% CI 1.22–10.64), P = 0.02] (Table 4).

Figure 1.

Kaplan–Meier curves of overall survival by the presence of retropharyngeal lymph node (RPLN) metastasis.

Figure 1.

Kaplan–Meier curves of overall survival by the presence of retropharyngeal lymph node (RPLN) metastasis.

Figure 2.

Kaplan–Meier curves of overall survival by the treatment modality and the presence of RPLN metastases.

Figure 2.

Kaplan–Meier curves of overall survival by the treatment modality and the presence of RPLN metastases.

DISCUSSION

Hypopharyngeal cancer can actually metastasize to the RPLNs, and similarly nasopharyngeal and oropharyngeal carcinomas (12). However, physical examination is insufficient for detecting RPLN involvement, such that RPLN involvement is determined using imaging studies during pretreatment evaluation. Mancuso et al. (9,10) first systematically evaluated cervical and RPLN metastasis by CT for patients with head and neck cancers and concluded that CT of the cervical nodes was a valuable adjunct in the staging of head and neck cancer. There is some interest in the use of ultrasonography for RPLN detection, which could be valuable for monitoring the response during radiotherapy or for follow-up purposes (13). The usefulness of fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT in delineating RPLNs has also been reported in some literature (14,15). In 2010, Chan et al. (16) reported that 18F-FDG PET is helpful in detecting RPLN metastasis in hypopharyngeal cancer. However, there is no doubt that CT and MRI play major roles in the clinical setting.

It is uncertain as to which radiological criteria most accurately diagnose RPLN metastasis, since there are only limited data to date. Thus, in the present study, we considered RPLNs metastatic when they measured 10 mm or larger or showed any findings suggestive of central necrosis, a commonly used criteria. Some reports investigated the evaluation criterion of RPLN metastasis specifically in patients with nasopharyngeal carcinoma (17–19). One of these radiological criteria advocated for assessing RPLN in nasopharyngeal cancer were nodes with a minimal axial diameter of 6 mm or larger, any node with central necrosis, groups of two or more RPLNs or any medial RPLN (19). Only one study has focused on the radiological–histopathological correlation of RPLN in patients with hypopharyngeal carcinoma. In that report, it was observed that the diagnosis of RPLN metastasis by CT scan was 100% sensitive, specific and accurate, and that MRI demonstrated a sensitivity, specificity and accuracy of 83.3, 100 and 97.0%, respectively (5). However, only six patients with metastatic RPLNs were included in their study. Yoshimoto and Kawabata (6) found 41 patients with RPLN metastasis in their surgical series. Preoperative imaging revealed positive RPLNs for 32 patients, however, positive nodes were too small to be detected on CT or MRI in other 9 patients. Thus, the radiological–histopathological correlation of RPLNs has yet to be determined.

We found that 7.9% of patients had RPLN metastasis. There were some discrepancies with regard to the incidence of RPLN metastasis. In their surgical series, Mori et al. (20) reported that metastasis to RPLNs was seen in 5.4% of patients. Yoshimoto and Kawabata (6) reported in their radiological and surgical experience, that metastasis to RPLNs was seen in 54 of 366 patients (14.8%). Amatsu et al. (7) reported that 18% of hypopharyngeal cancer patients who received RPLN dissection possessed metastatic foci. Hasegawa and Matsuura (4) found that 62% of patients with stages III and IV hypopharyngeal cancer had positive RPLNs. Furthermore, Kamiyama et al. (8) reported that 13.2% of patients incurred RPLN metastasis during their follow-up period. Although these percentages might have been derived from a selection bias in the literature, the reason for this variable incidence of RPLN metastasis is not clear.

We have also demonstrated that primary tumors originating from the posterior wall had significantly higher incidence of RPLN metastasis as shown by others (6–8). Thus, it was considered that patients with posterior wall tumors should be carefully evaluated for RPLN metastasis, both clinically and radiologically. Although several groups have shown an association between advanced T- and N-stages and RPLN involvement (6,7), we failed to demonstrate such a correlation, probably due to the low incidence of RPLN metastasis when compared with these reports.

As for the therapeutic value, some groups have advocated RPLN dissection for advanced hypopharyngeal cancer (4,7,8). On the other hand, another study suggested that RPLN metastasis does not affect disease control or patient survival (21). In case of definitive radiotherapy, no evidence exists concerning the treatment of RPLN but, nevertheless, recent textbooks of radiotherapy recommend including RPLNs in the treatment volume (22–24). In addition, two reports on the usefulness of FDG-PET/CT in staging hypopharyngeal cancer suggested that special attention be paid to RPLNs when delineating the target volume in radiation therapy (14,15). We also recommend the treatment of RPLNs when the primary tumor originates from the posterior wall. However, whether the treatment of RPLNs would improve the clinical outcomes should be confirmed in a future large study.

We have suggested RPLN metastasis to be an early indicator of distant metastasis. Similar associations between RPLN metastasis and distant metastasis in head and neck cancers have been previously demonstrated (25). In fact, the overall and cause-specific survival rates of patients with metastatic RPLN were far poorer than those of patients without metastasis in our study. These results were in accordance with a previous series on hypopharyngeal cancer (6). Furthermore, RPLN metastasis was described as a poor prognostic factor for head and neck cancers in several studies (25,26). Although some groups have failed to demonstrate the prognostic significance of RPLN involvement (7,21), we should emphasize that hypopharyngeal cancer with metastatic RPLNs should be managed with systemic chemotherapy, as more than half of our patients with RPLN metastasis experienced distant metastasis soon after the completion of treatment.

CONCLUSIONS

We have demonstrated that patients with hypopharyngeal cancer, especially those with posterior wall tumors, are at a high risk for RPLN involvement. Patients with RPLN metastasis developed distant metastases frequently, and showed dismal outcomes.

Conflict of interest statement

None declared.

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