選擇性第一到第三區頸部淋巴廓清之最低淋巴摘除數量

Head & Neck-01 選擇性第一到第三區頸部淋巴廓清之最低淋巴摘除數量 Minimal Lymph Node Yield in Elective Level I-III Neck Dissection Jason D. Pou, MD; Blair M. Barton, MD; Claire M. Lawlor, MD; Christopher H. Frederick, BS; Brian A. Moore, MD, FACS; Christian P. Hasney, MD, FACS 臺中榮民總醫院耳鼻喉頭頸部劉時安醫師 Commentary 根據 GLOBOCAN 2012 年的統計報告, 全球每年頭頸癌新增個案約 60 萬, 死亡個案則有 32 萬 5 千例 頸部淋巴轉移是頭頸癌重要之預後因子, 一旦有頸部淋巴轉移, 存活率將會減少一半, 由於臨床無淋巴轉移 (cn0) 之潛藏性淋巴轉移機率仍有 15% 到 20%, 所以在特定高危險族群之 cn0 頭頸癌患者 ( 如 : 原發腫瘤大於 2 公分 侵犯深度超過 4 公厘 有神經周圍或血管淋巴之侵犯等 ) 會建議施行選擇性第一到第三區 ( 肩胛舌骨上 ) 之頸部淋巴廓清手術 淋巴結清除範圍曾在大腸直腸癌 乳癌 膀胱癌 陰莖癌 胃癌 及食道癌的研究中被探討過, 結論均認為摘除一定數量之淋巴結與良好預後是有相關的 Ebrahimi 等在他們對於口腔癌的研究中發現如果淋巴結摘除數量少於 18 顆患者, 整體存活率及疾病別存活率 (disease-specific survival) 會較差 另一篇研究則發現在病理報告無淋巴轉移的口腔癌患者, 頸部淋巴結摘除數量愈多, 存活率愈高 本篇研究欲探討臨床無頸部淋巴轉移之頭頸癌患者接受選擇性第一到第三區頸部淋巴廓清手術後, 淋巴摘除數量與病理陽性之間的相關性 作者收集從 2004 年到 2015 年在 Ochsner Clinic Foundation 因頭頸癌接受頸部淋巴廓清手術之患者, 排除條件為 : 淋巴摘除數量不明 原發部位在鼻竇及鼻腔 臨床或影像學有頸部淋巴轉移 及廓清範圍超過第一到第三區者, 所有患者均以 2010 年版 AJCC 重新分期 研究最後共納入 98 例頭頸癌患者 ( 包括 : 皮膚癌 腮腺癌 口腔癌 及口咽癌 ), 總計 118 側的第一到第三區頸部淋巴廓清 ( 所以有 20 例接受雙側手術 ), 摘除的淋巴結數量平均每側為 21.15 顆 ( 標準差 :12.9 顆 ), 其中病理陽性淋巴結共有 28 側 (23.73%),12 側在病理分期為 N2 以上 (10.17%) ( 註 : 作者並沒有特別提到當二側都為 N1 時是否歸為 N2, 且摘要與本文的數字有異 ), 當淋巴摘除數量達 35 顆以上,N2 的比例最高 (21.05%), 在淋巴摘除數量 18 到 25 顆組別的病理陽性率最高 (36%), 如以 18 顆為界限, 淋巴摘除數量 18 顆以上 ( 含 ) 較 18 顆以下有較高之病理陽性率 這篇文章結論是在臨床或影像學無頸部淋巴轉移之頭頸癌患者在接受選擇性頸部淋巴廓清手術時, 建議最少應取得 18 顆淋巴結, 才有較高的機會找到潛藏性淋巴轉移 臨床分期固然重要, 但病理分期能讓頭頸科醫師更精確地擬訂治療計劃及評估預後 正確的病理分期, 有賴病理科醫師的判讀, 當然這還牽涉到標本處理 ( 每顆淋巴結要切多少片 染色是否確實 ) 及判讀醫師之經驗等因素, 不過前提是頭頸外科醫師要能取得真正有問題的淋巴結才行, 所以當臨床或影像學看不到淋巴結時, 清除的範圍及數量就相當重要, 統計學的原理是當取樣樣本數愈大時愈能代表母群體, 當摘除的淋巴結沒有到一定數量, 要說患者是 N0, 相信大家也會有點心虛吧 關鍵字 : 淋巴結摘除數量, 第一到第三區頸部淋巴廓清, 肩胛舌骨上 Comment on Laryngoscope, 127:2070 2073, 2017 59

The Laryngoscope VC 2017 The American Laryngological, Rhinological and Otological Society, Inc. Minimum Lymph Node Yield in Elective Level I III Neck Dissection Jason D. Pou, MD; Blair M. Barton, MD; Claire M. Lawlor, MD; Christopher H. Frederick, BS; Brian A. Moore, MD, FACS; Christian P. Hasney, MD, FACS Objectives/Hypothesis: Unlike lymphadenectomy at other sites, there is no discrete lymph node count defining an adequate neck dissection. The purpose of this study was to determine the minimum lymph node yield (LNY) of an elective level I III neck dissection required to reliably capture any positive nodes present in these nodal basins. Study Design: Retrospective single-institution analysis. Methods: All patients with the diagnosis of head and neck squamous cell carcinoma who underwent elective level I III neck dissection between 2004 and 2015 at our institution were analyzed. Preoperatively, patients had no clinical or radiographic evidence of lymphadenopathy. Patients with unknown number of lymph nodes on pathology report were excluded. Age, gender, race, history of radiation, tumor subsite, stage, surgeon, LNY, and number of positive nodes were recorded; bilateral neck dissections were reported separately. Results: One hundred eighteen level I III neck dissections met criteria and were included in the study. Mean LNY was 21.15, and metastatic disease was present in 24.5% of cases, with 8.4% of cases being N2. The highest portion of positive lymph nodes was present in the group with 18 to 24 lymph nodes (36%), which was significantly higher than the group with <18 (14.89%) (P 5.044). Conclusions: Although there is no accepted minimum for LNY in level I III neck dissection, at least 18 nodes may be considered an adequate LNY. Such a yield reliably allows for capture of occult disease within these nodal basins. Key Words: Lymph node yield, level I III neck dissection, supraomohyoid. Level of Evidence: 4. Laryngoscope, 127:2070 2073, 2017 INTRODUCTION Noncutaneous head and neck cancer makes up approximately 3% of all cancers in the United States, with oral cavity squamous cell carcinoma (SCCA) accounting for 2.4% of all newly diagnosed cancer. 1,2 Despite advances in treatment and reconstruction, mortality continues to remain high for oral cavity SCCA due to significant occurrence of distant metastasis and metachronous malignancies. 2 4 Oral cavity SCCA has a high risk of cervical metastasis, with up to 50% of patients having pathologically positive regional disease at the time of diagnosis. 4 Nonmelanoma skin cancer is the most commonly diagnosed malignancy, and its incidence increases as the population ages. 5 SCCA makes up for 20% of nonmelanoma skin cancer of the head and neck regions. 6 One percent to 5% of cases of SCCA of the scalp and face will develop parotid basin lymph node metastasis. 7,8 Of these From the Department of Otolaryngology Head and Neck Surgery (J.D.P., B.B., C.L., C.H.F., B.A.M., C.P.H.), Tulane University School of Medicine, New Orleans, Louisiana; Department of Otorhinolaryngology (B.A.M., C.P.H.), Ochsner Clinic Foundation, New Orleans, Louisiana, U.S.A. Editor s Note: This Manuscript was accepted for publication January 27, 2016. Original data were collected at the Department of Otorhinolaryngology, Ochsner Clinic Foundation, New Orleans, Louisiana, U.S.A. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Jason D. Pou, MD, 1430 Tulane Avenue, New Orleans, LA 70112. E-mail: jpou@tulane.edu DOI: 10.1002/lary.26545 cases, 35% to 50% will have occult nodal disease in the neck, with predominant involvement of level II. 8 Presence of metastatic lymph nodes is an important prognostic factor in head and neck SCCA, decreasing survival by up to 50%. 9 Modified radical neck dissection is generally indicated for clinically positive lymphadenopathy in head and neck SCCA. 10 Elective neck dissection is indicated in the clinically node negative (cn0) neck for those with 15% to 20% risk of cervical metastasis. 11,12 Elective level I III (supraomohyoid) neck dissection is indicated for the majority of oral cavity SCCA and select cutaneous SCCA with high-risk features due to the significant risk of occult nodal disease. 8,13 Highrisk features for cutaneous lesions include primary lesions with a diameter >2 cm; >4-mm depth; involvement of the auricle; poorly differentiated grade; and microvascular, lymphatic, or perineural invasion. 14 Oral cavity SCCA with depth of 4 to 5 mm are considered high-risk for nodal metastasis, and elective neck dissection offers improved overall survival than therapeutic dissection after nodal relapse. 8,15 Extent of lymphadenectomy has been analyzed in other areas including colorectal, 16 breast, 17,18 bladder, 19 penile, 20 gastric, 21 and esophageal 22 cancer, and a minimum LNY has been established that correlates with improved survival. Currently, there is no discrete lymph node count defining an adequate level I III neck dissection; however, interest in LNY has recently increased in the field of otolaryngology. Ebrahimi et al. concluded that LNY <18 was associated with reduced overall and 60

Specimens were stratified into LNY groups 1 to 9, 10 to 17, 18 to 25, 26 to 35, and >35. Proportion of N0, N1, and N2 specimens were compared among the groups (Fig. 1). Proportion of specimens with positive verses negative lymph nodes was then compared among the groups (Fig. 2). Proportions of positive lymph nodes among groups were analyzed with two-tailed z score tests. LNY means were analyzed using two-tailed t tests. P values <.05 were considered significant. Statistical analysis was completed using SAS software version 9.3 (SAS Institute Inc., Cary, NC). The study was approved by the institutional review board of the senior author s primary institution. Fig. 1. N stage by extent of nodal sampling in cn0 level I III neck dissection. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.] disease-specific survival in oral cavity SCCA. 23 A recent study by Lemieux et al. reported improved overall survival for patients with pathologically N0 (pn0) oral cavity SCCA with greater LNY. 13 Our study focused on patients with cn0 SCCA of the head and neck who underwent specifically elective level I III neck dissection. The purpose of this study was to determine the minimum LNY of an elective level I III neck dissection required to reliably capture any positive nodes present in these nodal basins. MATERIALS AND METHODS All patients with the diagnosis of head and neck SCCA who underwent cervical lymph node dissection between 2004 and 2015 with the Otolaryngology Head and Neck Surgery Department at the Ochsner Clinic Foundation where analyzed. Patient gender, race, age at time of procedure, date of procedure, prior radiation therapy, primary surgeon, and concurrent procedure performed were documented. The pathology reports were reviewed, and the levels dissected, the number of lymph nodes removed, and the number of positive nodes were documented. Bilateral neck dissections were recorded separately. Cases with an unknown number of lymph nodes on the pathology report were excluded. Cases of primary SCCA of the paranasal sinuses or nasal cavity were also excluded from the study. Patients with clinically or radiographically positive lymphadenopathy preoperatively were excluded from the study. Only neck dissections of levels I III were analyzed, which included patients with cutaneous, parotid, oral cavity, and oropharyngeal SCCA. Lymph nodes removed from other basins (i.e., parotid) were not included in the LNY. All cases were restaged with the 2010 American Joint Committee on Cancer criteria, and tumor subsite was recorded. The histopathological lymph node analysis technique remained the same over the length of the study. The shortest diameter of every node was measured. Every lymph node 4 mm or less identified in the specimen was cut into a single section and analyzed with light microscopy after hematoxylin and eosin (H&E) staining. Multiple sections were analyzed for all lymph nodes >4 mm in the shortest diameter. The number of sections varied based on the size of the node, but typically ranged from 2 to 3 sections. This is the standard H&E histopathological technique performed at our institution. RESULTS One hundred eighteen level I III neck dissections met criteria and were included in the study from 98 total patients. These patients were clinically N0 based on physical exam and preoperative computed tomography scan. Twenty patients in the study underwent bilateral level I III elective neck dissection. The mean (standard deviation) LNY was 21.15 (12.9), and metastatic disease was present in 23.73% of cases (28 specimens), with 10.17% of cases being N2 (12 specimens). Baseline data were comparable (Table I); however, nonwhite race had a significantly higher percentage of positive lymph nodes and N2 disease (P 5.044 and P 5.009, respectively). Patients with LNY >35 had the highest percentage of N2 disease (21.05%); however, this was not significantly different from the group with LNY 26 to 35 (P 5.478). The highest proportion of positive lymph nodes was present in the group with 18 to 25 lymph nodes (36%), which was significantly higher than the two groups combined with <18 lymph nodes (14.89%) (P 5.044). Specimens with 18 or more lymph nodes had a significantly higher proportion of positive nodes compared to those with <18 lymph nodes (P 5.032). LNY >25 did not yield in a higher proportion of positive lymph nodes (Fig. 2). DISCUSSION Lymph node metastasis is a crucial prognostic factor in patients with head and neck SCCA. 9 Despite advances in diagnostic imaging, currently there are no imaging Fig. 2. Proportion of N1 disease by number of nodes retrieved in cn0 level I III neck dissection. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.] 61

TABLE I. Baseline Data for Level I III Dissections in cn0 Specimens. LNY P Value No. N1 (%) P Value N2 (%) P Value Female 19.24.208 42 12 (28.57%).358 4 (9.52%).865 Male 22.37 76 16 (21.05%) 8 (10.53%) White 21.35.815 105 22 (20.95%).044 8 (7.62%).009 Nonwhite 20.46 13 6 (46.15%) 4 (30.77%) Age >55 years 20.43.160 95 22 (23.16%).764 9 (9.47%).61 Age 55 years 24.65 23 6 (26.09%) 3 (13.04%) Prior XRT 17.92.146 25 8 (32.00%).271 4 (16.00%).276 No XRT 22.15 93 20 (21.51%) 8 (8.6%) Oral cavity 21.06.528 85 19 (22.35%).541 10 (11.76%).324 Oropharynx 16.5 6 2 (33.33%) 1 (16.67%) Cutaneous 22.93 27 7 (25.93%) 1 (3.70%) T1 22.59.586 29 8 (27.59%).231 3 (10.34%).273 T2 20.04 53 10 (18.87%) 5 (9.43%) T3 19.68 22 6 (27.27%) 3 (13.64%) T4 26.36 11 3 (27.27%) 1 (9.09%) Tx 22.67 3 1 (33.33%) 0 (0%) LNY 5 lymph node yield; XRT 5 radiation therapy. modalities capable of accurately detecting occult disease in the cn0 neck. 24,25 Cervical lymphadenectomy remains the gold standard for nodal staging in cn0 patients with high-risk head and neck SCCA. 11,12,24 The accuracy of surgical staging in the cn0 neck depends on the number of lymph nodes removed and the sensitivity of the pathological methods for detecting occult metastatic disease. 13 The traditional histopathological approach to analyzing lymph nodes in neck dissection specimens consists of obtaining a single, longitudinal section from the center of each individual lymph node. The pathologist performs an H&E stain, then analyzes the entire section under light microscopy for deposits of metastatic disease. 26 This method has long been accepted and is widely used, compromising some loss of thoroughness for practicality of examination. 27 Micrometastatic disease is defined as evidence of metastasis deposits not detected by standard H&E microscopy but subsequently discovered with a more sensitive histopathological technique. 28 Approximately 25% of patients with cn0 head and neck SCCA will have micrometastasis <3 mm in the elective neck dissection specimen. 29 Serial section H&E staining at 3 to 4 lm of the entire lymph node is a more time consuming analysis but demonstrates detection of metastatic disease in 2.2% of pn0 specimens performed by standard analysis. 29,30 Cytokeratin immunohistochemical analysis can detect a single epithelial cancer cell in a lymph node 24 ; several studies have demonstrated a wide detection rate of micrometastatic disease using this technique. 24,27 Prognostic implications of micrometastatic disease are not fully understood, but recent studies suggest the increased detection of micrometastatic disease with higher LNY may account for improved overall survival. 13 Although there is no current minimum nodal count established in the neck dissection, there has been increased investigation in LNY in the field of otolaryngology. In 2003, Agrama and colleagues analyzed nodal yield in T1 and T2 head and neck SCCA and discovered LNY >20 corresponded with increased cervical metastasis. 31 This study analyzed all neck dissections and did not distinguish levels of dissection or preoperative nodal status. More recently, investigators have examined the prognostic significance of LNY in oral cavity SCCA. The ratio of positive to negative nodes removed in a neck dissection is an independent predictor of survival in patients with oral cavity SCCA. 32 Ebrahimi et al. performed a multicenter retrospective multivariable analysis among cn0 patients with oral cavity SCCA and concluded that LNY <18 was associated with decreased disease-free survival. 23 And more recently, Lemieux et al. investigated LNY in pn0 patients with oral cavity SCCA and discovered improved overall survival in patients with increased LNY. 13 This is the first study to specifically analyze LNY in level I III neck dissection in cases of cn0 head and neck SCCA. A significantly higher proportion of occult metastatic disease was detected by our institution s standard microscopic histological analysis among specimens with 18 or more lymph nodes compared to those with <18 lymph nodes (P 5.033). This demonstrates that LNY <18 in level I III neck dissections may fail to capture occult metastatic disease, leading to understaging and, possibly, underutilization of crucial adjuvant treatment modalities. The proportion of positive disease did not increase with higher LNY groups, thus supporting the minimum nodal yield of 18, as proposed by recent investigators, to deem a level I III lymphadenectomy adequate. There are several relevant limitations in the present study. Because we are analyzing multiple sites and stages of SCCA in the head and neck, minimal information can be obtained regarding prognostic implications of 62

LNY in this study. Our sample size is small compared to recent investigations; thus, separating these patients by stage and cancer subsite depowers the analysis below significance. Another potential limitation is the pathological technique for analyzing specimens. Although the institution s standard modality did not change over the course of this study, multiple pathologists participated in the analysis allowing for minor differences in microscopic techniques, potentially altering the LNY and detection of metastatic disease. CONCLUSION Although there is no accepted minimum for LNY in the elective level I III neck dissection, at least 18 nodes may be considered an adequate LNY. Such a yield reliably allows for capture of occult disease within these nodal basins. Further investigation is necessary to establish if incorporation of a minimum LNY in the level I III lymphadenectomy will improve clinical outcomes. BIBLIOGRAPHY 1. Cancer Facts and Figures 2016. American Cancer Society website. Available at: http://www.cancer.org/acs/groups/content/@research/documents/ document/acspc-047079.pdf. Accessed September 4, 2016. 2. Koloutsos G, Vahtsevanos K, Kyrgidis A, Kechagias N, Triaridis S, Antoniades K. Neck dissection in relation with disease-free, disease-specific, and overall survival of patients with squamous cell cancer of the oral cavity. J Craniofac Surg 2014;25:1992 1997. 3. Kyrgidis A, Nokolaou A, Rachvitsas D, et al. Demographic clinical and histopathological characteristics of oral cavity cancer: survival analysis in a single center retrospective study. Hell Otorhinolaryngol Head Neck Surg 2008;33:8 18. 4. Shin YS, Koh YW, Kim SH, Choi EC. Selective neck dissection for clinically node-positive oral cavity squamous cell carcinoma. Yonsei Med J 2013;54:139 144. 5. Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol 2010; 146:283 287. 6. Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med 2001;344:975 983. 7. Herman MP, Amdur RJ, Werning JW, Dziegielewski P, Morris CG, Mendenhall WM. Elective neck management for squamous cell carcinoma metastatic to the parotid area lymph nodes. Eur Arch Otorhinolaryngol 2016;273:3875 3879. 8. O Hara J, Ferlito A, Takes RP, et al. Cutaneous squamous cell carcinoma of the head and neck metastasizing to the parotid gland a review of current recommendations. Head Neck 2011;33:1789 1795. 9. Marchiano E, Patel TD, Eloy JA, Baredes S, Park RW. Impact of Nodal Level Distribution on Survival in oral cavity squamous cell carcinoma: A population-based study. Otolaryngol Head Neck Surg. 2016;155:99 105. 10. Kowalski LP, Sandabria A. Elective neck dissection in oral carcinoma: a critical review of the evidence. Acta Otorhinolaryngol Ital 2007;27:113 117. 11. Weiss MH, Harrison LB, Isaacs RS. Use of decision analysis in planning a management strategy for the stage N0 neck. Arch Otolaryngol Head Neck Surg 1994;120:699 702. 12. Pillsbury HC, Clark M. A rational for therapy of the N0 neck. Laryngoscope 1997;107:1294 1315. 13. Lemieux A, Kedarisetty S, Raju S, Orosco R, Coffey C. Lymph node yield as a predictor of survival in pathologically node negative oral cavity carcinoma. Otolaryngol Head Neck Surg 2016;154:465 472. 14. Moore BA, Weber RS, Prieto V, et al. Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck. Laryngoscope 2005; 115:1561 1567. 15. D Cruz AK, Vaish R, Kapre N, et al. Elective verses therapeutic neck dissection in node-negative oral cancer. N Engl J Med 2015;373:521 529. 16. Chen SL, Bilchik AJ. More extensive nodal dissection improved survival for stages I to III of colon cancer. Ann Surg 2006;244:602 610. 17. Somner JEA, Dixon JMJ, Thomas JSJ. Node retrieval in axillary lymph node. dissections: recommendations for minimum numbers to be confident about node negative status. J Clin Pathol 2004;57:845 848. 18. Weir L, Speers C, D yachkova Y, et al. Prognostic significance of the number of axillary lymph nodes removed in patients with node-negative breast cancer. J Clin Oncol 2002;20:1793 1799. 19. Wright JL, Lin DW, Porter MP. The association between extent of lymphadenectomy and survival among patients with lymph node metastases undergoing radical cystectomy. Cancer 2008;112:2401 2408. 20. Johnson T V, Hsiao W, Delman KA, et al. Extensive inguinal lymphadenectomy improves overall 5-year survival in penile cancer patients: results from the Surveillance, Epidemiology, and End Results program. Cancer 2010;116:2960 2966. 21. Volpe CM, Driscoll DL, Douglass HO. Outcome of patients with proximal gastric cancer depends on extent of resection and number of resected lymph nodes. Ann Surg Oncol 2000;7:139 144. 22. Peyre CG, Hagen JA, DeMeester SR, et al. The number of lymph nodes removed predicts survival in esophageal cancer: an international study on the impact of extent of surgical resection. Ann Surg 2008;248:549 556. 23. Ebrahimi A, Clark JR, Amit M, et al. Minimum nodal yield in oral squamous cell carcinoma: defining the standard of care in a multicenter international pooled validation study. Ann Surg Oncol 2014;21: 3049 3055. 24. Cho JH, Lee YS, Sun D, et al. Prognostic impact of lymph node micrometastasis in oral and oropharyngeal squamous cell carcinoma. Head Neck 2016;38(suppl 1):E1777 E1782. 25. Ferlito A, Shaha AR, Rinaldo A. The incidence of lymph node micrometastases in patients pathologically staged N0 in cancer of oral cavity and oropharynx. Oral Oncol 2002;38:3 5. 26. Devaney SL, Ferlito A, Rinaldo A, Devaney KO. The pathology of neck dissection in cancer of the larynx. ORL J Otorhinolaryngol Relat Spec 2000;62:204 211. 27. Devaney KO, Rinaldo A, Ferlito A. Micrometastases in cervical lymph nodes from patients with squamous carcinoma of the head and neck: should they be actively sought? Maybe. Am J Otolaryngol 2007;28: 271 274. 28. Enepekides DJ, Sultanem K, Nguyen C, et al. Occult cervical metastases: immunoperoxidase analysis of the pathologically negative neck. Otolaryngol Head Neck Surg 1999;120:713 717. 29. Van Der Brekel MW, Van Der Waal I, Meijer CJ, Freeman JL, Castelijns JA, Snow GB. The incidence of micrometastases in neck dissection specimens obtained from elective neck dissections. Laryngoscope 1996;106: 987 991. 30. Barrera JE, Miller ME, Said S, Jafek BW, Campana JP, Shroyer KR. Detection of occult cervical micrometastases in patients with head and neck squamous cell cancer. Laryngoscope 2003;113:892 896. 31. Agrama MT, Reiter D, Cunnane MF, et al. Nodal yield in neck dissection and the likelihood of metastases. Otolaryngol Head Neck Surg 2003;128: 185 190. 32. Shrime MG, Ma C, Gullane PJ, et al. Impact of nodal ratio on survival in squamous cell carcinoma of the oral cavity. Head Neck 2009;31: 1129 1136. 63