Effect of number and ratio of positive lymph nodes in hypopharyngeal cancer

ORIGINAL ARTICLE Effect of number and ratio of positive lymph nodes in hypopharyngeal cancer Yong-hong Hua, MD, PhD, Qiao-ying Hu, MD, * Yong-feng Piao, MD, Qiu Tang, MD, PhD, Zhen-fu Fu, MD Head and Neck Cancer Center, Zhejiang Cancer Hospital, Hangzhou, China. Accepted 10 December 2013 Published online 9 March 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23574 ABSTRACT: Background. The number and ratio of positive lymph nodes are important prognostic factors in gastric cancer, but there is little data reported in hypopharyngeal cancer. Methods. Medical data from 81 patients with hypopharyngeal cancer undergoing radical hypopharyngectomy and cervical lymph node dissection were reviewed. Results. The median survival time was 84, 54, 30, and 13 months in patients with N0, N1, N2, and N3, respectively, and 84, 51, and 17 months with positive lymph node ratios (N ratio) 0, <10%, and >10%, respectively. Of the 24 N1 patients, the 20 patients that had an N ratio <10% had a better prognosis than the 4 patients with an N ratio >10%. Similar data was seen for the N2 patients. Tumor (T) classification, adjuvant therapy, and N ratio were independent prognostic factors in multivariate analysis. Conclusion. The positive lymph node ratio is complementary to the current N classification system. VC 2014 Wiley Periodicals, Inc. Head Neck 37: 111 116, 2015 KEY WORDS: hypopharyngeal neoplasm, lymph nodes, metastatic lymph node ratio, prognosis, postoperative stage INTRODUCTION The prognosis is poor for patients with hypopharyngeal cancer because of frequent submucosal spread to regional lymph nodes, as well as distant metastasis at an early stage. The overall 5-year survival rate is only 20% to 40%. 1 For example, in the late 1990s in the United States, the 5-year disease-specific survival rate among 2939 cases from 769 hospitals was 33.4%. 2 The TNM classification system provides objective criteria to evaluate patient prognosis by incorporating information about the local tumor, cervical lymph node, and distant metastasis to evaluate the state of tumor dissimilation and guide therapeutic strategy. In the stage system of the Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC), the node (N) classification of hypopharyngeal cancer is based on clinical data, such as the diameter and location of palpable neck lymph nodes, but not the pathologic results of hypopharyngectomy and cervical lymph node dissection, despite the use of this data in other malignant tumors in which surgery is the primary treatment method. 3 5 For example, the original pathologic N classification in gastric cancer incorporated the anatomic location of lymph node metastasis (Japanese Research Society for Gastric Carcinoma, 1981). The UICC/AJCC later updated the pathologic N classification based on the number of metastatic lymph nodes, which provides a more accurate prognosis, is simpler, more reliable, and can be stratified. 6 However, this N *Corresponding author: Q. Hu, Head and Neck Cancer Center, Zhejiang Cancer Hospital, Hangzhou, China. E-mail: huqiaoying162@163.com classification is limited in patients with stage migration, especially when <15 lymph nodes are dissected. 7 Newer classification schemes incorporate the ratio between metastatic lymph nodes and the sum of dissected lymph nodes (N ratio), which more accurately reflects the degree of lymph node metastasis and reduces stage migration. Classification strategies for colon cancer also incorporate the number of metastatic lymph nodes, as those variables can be easily determined and used to predict prognosis. However, there are fewer studies on the of the number of metastatic lymph nodes in hypopharyngeal cancer. Therefore, the main contribution of this retrospective study was to evaluate the prognostic of quantifying the number of pathologic cervical lymph nodes for survival after curative cervical lymph node dissection for hypopharyngeal cancer. MATERIALS AND METHODS Patients Medical data of 81 patients with hypopharyngeal cancer undergoing radical hypopharyngectomy and cervical lymph node dissection at Zhejiang Cancer hospital between January 2000 and December 2005 were reviewed retrospectively. Patients enrolled in the study must have had: histologically proved squamous cell carcinoma (SCC); no preoperative chemotherapy/radiotherapy; and no evidence of distant metastasis. Neck lymph node dissection was performed by experienced surgeons. Of 81 eligible patients, there were 79 men (97.5%) and 2 women (2.5%). The median age was 60 years (range, 36 80 years). The specific sites of cancer onset were: pyriform sinus in 75 patients, posterior wall in 4 patients, and HEAD & NECK DOI 10.1002/HED JANUARY 2015 111

HUA ET AL. TABLE 1. Variable Patient characteristics. No. of patients Sex Male 79 Female 2 Age, y Median 60 (range, 36 80) Primary tumor site Pyriform sinus 75 Posterior wall 4 Postcricoid region 2 T classification T1 5 T2 11 T3 45 T4 20 N classification N0 17 N1 24 N2 34 N3 6 Clinical TNM classification I 1 II 6 III 30 IV 45 postcricoid region in 2 patients. Staging of primary tumors and metastatic lymph nodes were based on the TNM system of the 7th UICC/AJCC criteria. 8 The demographic and clinical characteristics of the patients are shown in Table 1. Treatment methods All patients underwent radical hypopharyngectomy and cervical lymph node dissection, with 46 of them also undergoing bilateral neck lymph node dissection. The scope of cervical dissection included bilateral level II, III, IV, and V, with 9 cases dissected at level I and 12 cases dissected at level VI. Thirty-one of them underwent unilateral lymph node dissection. The scope of cervical dissection included unilateral level II, III, IV, and V, and 5 cases were dissected at level I. Four of them underwent lateral neck lymph node dissection. The scope of dissection included unilateral level II, III, and IV. The unilateral dissection was adopted if they met these criteria: a pyriform sinus tumor located unilaterally in the hypopharynx, not across the midline; exclusion of metastasis to the contralateral cervical lymph node by clinical or imaging analysis; and clinical N classification <N2. Patients received bilateral lymph node dissection if the primary tumor was in the posterior wall or postcricoid regions. Four cases underwent lateral nodes dissection; 3 of them because of comorbid diseases and 1 of them because of advanced age. The use of adjuvant therapy after surgical resection depended on the pathology of the primary tumor and metastatic lymph nodes. The indications for postoperative radiotherapy were: primary tumor >T4, close margin, or more than 1 positive node. Postoperative radiotherapy was performed in 50 cases. Tumor bed doses ranged from 36 to 80 Gy, with a median dose of 60 Gy. Postoperative chemoradiotherapy was performed if there was a positive margin or extracapsular infiltration, with concurrent/adjuvant chemoradiotherapy performed in 29 cases: cisplatin plus fluorouracil regimen in 23 cases, fluorouracil plus bleomycin regimen in 4 cases, and vinorelbine plus cisplatin regimen in 2 cases. Variables Patients were grouped according to sex, age, tumor (T) classification, N classification, clinical stage, primary tumor site, and treatment method. Pathology information included the number of metastatic lymph nodes, the sum of the dissected nodes, the number of the involved region, the presence of extracapsular infiltration, and pathological grading of the primary tumor using the dissection classification sponsored by the American Head and Neck Society and the American Academy of Otolaryngology Head and Neck Surgery in 2002. 9 The N number was defined according to the number of metastatic nodes: N number 0 for no metastatic node, N number 1 for 1 to 3 metastatic nodes, and N number 2 for >3 metastatic nodes. N ratios were stratified by the ratio of metastatic nodes: N ratio 0 was defined as no metastatic node, N ratio 1 was the ratio of metastatic node <10%, and N ratio 2 was the ratio of metastatic nodes >10%. N-region was stratified by the involved region: N-region 0 was defined as no metastatic node, N-region 1 was 1 to 2 involved regions, and N- region 2 was >2 involved regions. Statistical analysis Data were analyzed using Statistical Package for the Social Sciences software (version 12.0; SPSS, Chicago, IL). The survival curve was obtained by the Kaplan Meier method. Differences between groups for each categorical variable were assessed using the log-rank test. The relationship between cervical lymph node metastasis and primary tumor-related variables were assessed using the chi-square test. Differences were considered to be significant at the 5% level. Independent variables predicting survival were evaluated by using the Cox proportional hazards model, and the 95% confidence interval was used to quantify the relationship between survival time and each independent factor. RESULTS Follow-up and survival rate All patients had follow-up after treatment at 3-month and 12-month intervals. The final date of follow-up was April 2012 and the follow-up rate was 93.8% (76 of 81). The median follow-up of the entire cohort was 48 months (range, 12 127 months). The 3-year and 5-year overall survival rates according to the Kaplan Meier method were 55% and 41%, respectively. The median survival time in cases treated with surgery alone and those with surgery followed by chemo/radiotherapy were 64 months and 24 months, which was significantly different (logrank test, chi-square 5 8.730; p 5.003). Relationship between cervical lymph node metastasis and primary tumor status Overall, 79.0% of patients (64 of 81) had cervical lymph node metastasis, 82.9% (53 of 64) in the 112 HEAD & NECK DOI 10.1002/HED JANUARY 2015

POSITIVE LYMPH NODES IN HYPOPHARYNGEAL CANCER TABLE 2. Characteristics Distribution of cervical lymph node metastasis in the cohort. No. of patients by lymph node metastasis (%) p Sex Male 62 (78.5).460 Female 2 (100) Age, y <60 33 (82.5).446 >60 31 (75.6) T classification T1 1 (20.0).002 T2 7 (63.6) T3 38 (84.4) T4 18 (90.0) Tumor location Pyriform sinus 60 (0.8).577 Posterior wall 3 (75.0) Postcricoid region 1 (50.0) Differentiation High 29 (72.5).363 Middle 18 (85.8) Low 17 (85.0) unilateral neck, and 17.1% (11 of 64) in the bilateral neck. The median total lymph node number was 47 (range, 3 95; mean, 46.9) per patient, and the median metastatic lymph node number was 2 (range, 0 17; mean, 3.29). There were 267 metastatic lymph nodes in total: 2 of them located in level I (0.8%), 98 of them located in level II (36.7%), 91 of them located in level III (34.1%), 63 of them located in level IV (23.6%), 8 of them located in level V (2.9%), and 5 of them located in level VI (1.9%). There was a positive correlation between the risk of lymph node metastasis and the diameter of the primary tumor. T1 tumors showed cervical lymph node metastasis in 20% of patients; however, T3 and T4 tumors showed metastasis in 84.4% and 90% of patients (Table 2). Lymph node metastasis was not associated with sex, age, tumor location, and pathologic grading (Table 2). Univariate analysis for prognostic factors of overall survival The factors influencing the 5-year survival rate were T classification, N classification, TNM stage, and adjuvant therapy (Table 3), as did all factors related with cervical lymph node metastasis, including the number of metastatic lymph nodes, the number of involved regions, extracapsular infiltration, and the N ratio. The relationship between the current N classification and N ratio/n number were analyzed by Kaplan Meier (Figure 1). Patients with the same N classification were stratified according to N ratio: 24 patients with N ratio 1 had a better prognosis than the 4 patients with N ratio 2, with median survival times of 62 months and 19 months, respectively. In N2 classification, the median survival time was 45 months in 21 patients with N ratio 1, and 18 months in N ratio 2. There was no significant relationship between N classification and N number. Subgroup analysis is shown in Tables 4 and 5. Multivariate analysis The prognostic factors considered on univariate analysis were analyzed first by stepwise regression, including N number, N ratio, extracapsular infiltration, number of involved regions, T classification, N classification, clinical stage, and adjuvant treatment. Both T classification and the N ratio were independent prognostic factors for overall survival, as were adjuvant therapy and extracapsular infiltration (Table 6). TABLE 3. Relationship between clinicopathologic factors and prognosis in hypopharyngeal cancer. Clinicopathologic factors No. of patients (%) Median survival time, mo Chi-square p No. of metastatic nodes 0 17 (21.0) 84 19.746.000 1 3 35 (43.2) 51 >4 29 (35.8) 26 No. of involved regions 0 17 (21.0) 84 21.798.000 1 2 49 (60.5) 45 >3 15 (18.5) 23 Metastatic nodes ratio 0 17 (21.0) 84 32.033.000 <10% 43 (53.1) 51 >10% 21 (25.9) 17 Sex Male 79 (97.5) 44 0.212.645 Female 2 (2.5) 37 Age 60 40 (49.4) 58 0.353.552 >60 41 (50.6) 39 Primary tumor location Pyriform sinus 75 (92.6) 44 0.016.992 Posterior wall 4 (4.9) 41 Postcricoid region 2 (2.5) 34 T classification T1 5 (6.2) 100 26.4.000 T3 45 (55.6) 39 T4 20 (24.6) 24 N classification N0 17 (21.0) 84 28.074.000 N1 24 (29.6) 54 N2 34 (42.0) 30 N3 6 (7.4) 13 Adjuvant treatment No 28 (34.6) 24 8.730.003 Yes 53 (65.4) 64 Extracapsular infiltration No 50 (61.8) 66 36.370.000 Yes 31 (38.2) 20 Differentiation High 10 (12.3) 30 0.975.614 Middle 51 (63.0) 45 Low 20 (24.7) 37 Clinical TNM stage Stage I 1 II 6 (7.4) 100 23.182.000 Stage III 30 (37.0) 65 Stage IV 45 (55.6) 28 HEAD & NECK DOI 10.1002/HED JANUARY 2015 113

HUA ET AL. DISCUSSION Hypopharyngeal cancer and cervical lymph node metastasis As seen in most other SCC in the head and neck primaries, lymphatic drainage of hypopharyngeal cancer is predominantly to the cervical lymph nodes. However, hypopharyngeal cancer has the highest rate of regional lymph node metastasis among head and neck SCC with >50% of patients presenting with positive lymph nodes because of the extensive lymphatic network and early, diffuse submucosal infiltration. Here, 79% of 81 patients had cervical lymph node metastasis, consistent with another study showing a 75% incidence of lymph node metastasis at presentation. 10 These incident rates are higher because they are based on pathology not radiological detection, which is often insufficient to detect occult lymph nodes in the lateral neck (levels I V). 11 Although the cervical lymphatic drainage is complicated, the distribution of lymphatic metastases generally involves ipsilateral nodes at levels II or III. These firstechelon nodal groups are followed by level IV and contralateral level II and level III, with metastasis rarely seen in ipsilateral level V or at levels I or VI. In a 2044 patient study 12 of previously untreated SCCs of the head and neck, the 267 cases with hypopharyngeal cancer showed a frequency of lymphatic metastasis to level II or level III of 44.0% and 31.6%, respectively, with metastasis to level I accounting for <1%. The risk of contralateral lymph node metastasis increases greatly with ipsilateral lymph node metastasis. In our 64 cases with cervical nodes metastasis, 53 cases were in the ipsilateral neck and 11 in the bilateral neck, with no contralateral neck metastasis alone. Cervical positive nodes were distributed in levels II, III, and IV, with ratios of 36.7%, 34.1%, and 23.6%, respectively. FIGURE 1. Survival curves based on lymph node metastatic status: (A) the number of positive nodes, (B) the ratio of positive nodes, and (C) the number of involved levels. Cum survival, cumulative survival. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Primary tumor and cervical node metastasis Lymphatic vessel invasion increases with primary tumor diameter and invasion depth, as does the risk of lymph node metastasis. 13 Lymph node metastasis occurred more often in patients with poorly differentiated tumors, which may have a more progressive biological behavior. Primary tumors located in the media wall of the pyriform fossa are more likely to metastasize to the contralateral lymph node than lateral wall tumors because of differences in the drainage paths involved. 14 In our study, the diameter of the primary tumor significantly associated with the lymph node metastasis rate, but the location and differentiation of primary tumors did not influence the risk of lymph node metastasis. Our dataset only included 4 cases with tumors originating from the posterior wall and postcricoid region, which is too small for accurate statistical analysis. Further work with a larger sample size is needed. Prognosis and cervical nodes metastasis Metastatic lymph node status, including variables such as diameter, venous invasion, capsule, number, and positive lymph node ratio, is one of the most important prognostic factors in patients with malignant tumors. In the 114 HEAD & NECK DOI 10.1002/HED JANUARY 2015

POSITIVE LYMPH NODES IN HYPOPHARYNGEAL CANCER FIGURE 2. Influence of the interaction between N classification and N ratio in overall survival of patients with hypopharyngeal cancer: (A) N1 classification, (B) N2 classification. Cum survival, cumulative survival. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] UICC/AJCC staging system, clinical N classification is primarily based on the diameter and location of lymph nodes palpable or detectable by radiological scan. However, pathological N classification can depend either on the location of metastatic lymph nodes (lung cancer), the number of metastatic lymph nodes (gastric cancer), or both (breast cancer). 15 17 We therefore included both the number of positive lymph nodes and the anatomic location of metastatic nodes in our pathological N classification for hypopharyngeal cancer. Most metastatic nodes were located in levels II or III, so we stratified the number of positive regions as 0, 1 2, or >3. Univariate analysis showed that prognosis was influenced by the number of positive lymph nodes, the number of regions involved, and a positive N ratio. However, only the positive N ratio had prognostic in multivariate analysis. A positive N ratio also has prognostic in gastric cancer and colorectal cancer. Coimbra et al 18 reviewed the clinical and pathological data of 165 patients with gastric cancer who had undergone curative surgery. The patients were grouped into 4 arms according to the N ratio (the ratio between metastatic and dissected lymph nodes): N ratio 0 (NR0) corresponded to 0%, NR1 to the ratio between 1% and 9%, NR2 between 10% and 25%, and NR3 >25%. In accordance with TNM classification, N1 patients with NR1 had a 75.5% 5-year survival, whereas the NR2 group only had a 33% 5-year survival rate. We found that interaction between N classification and N ratio was an independent prognostic factor in multivariate analysis. The positive lymph node ratio, age, tumor diameter, and chemotherapy were independent prognostic factors in a study of 342 gastric patients, 19 with the number of positive lymph nodes being the best prognostic factor. In contrast, our multivariate analysis showed that the number of metastatic lymph nodes had no prognostic. In a study of 124 cases of local advanced rectal cancer, the N ratio predicted recurrence and survival more accurately than pathological N category, 20 suggesting that the pathological N classification and N ratio TABLE 4. N ratio. The relationship between the current N classification and TABLE 5. The relationship between the current N classification and N number. Median survival time* (no. of patients ) N ratio <10% N ratio >10% Chi-square p Median survival time* (no. of patients ) 0 <N number 3 N number >3 Chi-square p N1 62 (20) 19 (4) 6.082.014 N2 45 (21) 18 (13) 8.933.003 N3 28 (2) 9 (4) 3.386.049 N1 65 (18) 44 (6) 0.635.426 N2 33 (17) 26 (17) 2.538.111 N3 13 (6) - - * Month. Case. * Month. Case. HEAD & NECK DOI 10.1002/HED JANUARY 2015 115

HUA ET AL. TABLE 6. Multivariate Cox proportional hazards analysis. 95% CI for HR Variable b Wald p HR Lower Upper N number 20.344 0.762.383 0.709 0.327 1.536 No. of involved regions 0.077 0.108.742 1.080 0.681 1.712 N ratio 0.991 5.630.018 2.694 1.188 6.107 T classification 0.834 12.212.000 2.303 1.442 3.677 N classification 20.430 1.085.298 0.651 0.290 1.461 Adjuvant treatment 20.306 4.208.040 0.736 0.550 0.986 Clinical TNM stage 0.413 0.916.338 1.511 0.649 3.516 Extracapsular infiltration 0.802 4.394.036 2.231 1.054 4.725 Abbreviations: CI, confidence interval; HR, hazard ratio. should be considered together when estimating the risk of disease recurrence in patients with rectal cancer. In this study, we found that patients with the same N classification had different prognoses. The significant heterogeneity in survival, even for patients at the same UICC/AJCC stage, makes it challenging to predict prognosis and make treatment decisions. The N ratio may be helpful to further stratify these patients within the current N classification system. We found that the N ratio provided additional information within the N classification system to inform prognosis. CONCLUSION We studied the relationship between cervical lymph node metastasis and prognosis in 81 hypopharyngeal cancer cases undergoing radical tumorectomy and neck lymph node dissection. In general, lymphatic metastasis is very common in patients with hypopharyngeal cancer, and lymph node status is a primary prognostic factor. Univariate analysis showed that survival was influenced by the number of metastatic nodes, the number of involved regions, and the ratio between the number of metastatic nodes and dissected ones, but only the metastatic lymph node ratio retained statistical significance in multivariate analysis with the Cox proportional hazard model. 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