Nodal Disease Burden for Early-Stage Oral Cancer | Head and Neck Cancer | JAMA Otolaryngology–Head & Neck Surgery | JAMA Network
[Skip to Navigation]
Sign In
Figure 1.  Diagram of Study Patients
Diagram of Study Patients

The diagram depicts by nodal status at initial presentation, initial treatment types, and nodal status at initial treatment and during follow-up. cN0 indicates clinically node-negative disease; cN+, clinically node-positive disease; END, elective neck dissection; LE, local excision; OSCC, oral squamous cell carcinoma; pN0, pathologically proven node-negative disease at surgery; pN+, pathologically proven node-positive disease at surgery or during follow-up; RF, regional failure (development of pN+ in patients with cN0 disease at follow-up); and RT, radiotherapy. Dashed line indicates clinical follow-up after initial treatment.

Figure 2.  Kaplan-Meier Analysis of 5-Year Overall Survival (OS) and Disease-Specific Survival (DSS)
Kaplan-Meier Analysis of 5-Year Overall Survival (OS) and Disease-Specific Survival (DSS)

Includes patients with clinically node-negative (cN0) disease at presentation. END indicates elective neck dissection; LE, local excision; and RT, radiotherapy. Differences in survival time between groups were tested by log-rank test, with P < .05 considered as significant.

Figure 3.  Disease-Specific Survival (DSS) and Cumulative Incidence of Regional Failure (RF)
Disease-Specific Survival (DSS) and Cumulative Incidence of Regional Failure (RF)

Includes 322 patients with clinically node-negative (cN0) disease who received local excision without prophylactic neck treatment. Outcomes (denoted →) include continued cN0 disease and pathologically proven node-positive disease (pN+). Dashed line indicates 95% CI.

aIndicates log-rank test of difference at 2, 3, and 5 years of P < .001.

Figure 4.  Overtreatment or Undertreatment of Patients by Depth of Invasion (DOI) of Tumor
Overtreatment or Undertreatment of Patients by Depth of Invasion (DOI) of Tumor

Includes patients with clinically node-negative disease (cN0). Outcomes (denoted →) include continued cN0 disease and pathologically proven node-positive disease (pN+). Overtreatment is calculated as the total number of the cN0→cN0 group at and above the corresponding cutoff divided by the total number of treated patients at and above the corresponding DOI; undertreatment, the total number of the cN0→pN+ group below the corresponding cutoff divided by the total number of patients below the corresponding DOI.

Table.  Patient Demographic and Clinicopathologic Characteristics
Patient Demographic and Clinicopathologic Characteristics
1.
Johnson  NW, Jayasekara  P, Amarasinghe  AA.  Squamous cell carcinoma and precursor lesions of the oral cavity: epidemiology and aetiology.  Periodontol 2000. 2011;57(1):19-37.PubMedGoogle ScholarCrossref
2.
Huang  TY, Hsu  LP, Wen  YH,  et al.  Predictors of locoregional recurrence in early stage oral cavity cancer with free surgical margins.  Oral Oncol. 2010;46(1):49-55.PubMedGoogle ScholarCrossref
3.
Ho  CM, Lam  KH, Wei  WI, Lau  SK, Lam  LK.  Occult lymph node metastasis in small oral tongue cancers.  Head Neck. 1992;14(5):359-363.PubMedGoogle ScholarCrossref
4.
Le Tourneau  C, Velten  M, Jung  GM, Bronner  G, Flesch  H, Borel  C.  Prognostic indicators for survival in head and neck squamous cell carcinomas: analysis of a series of 621 cases.  Head Neck. 2005;27(9):801-808.PubMedGoogle ScholarCrossref
5.
Woolgar  JA.  Histopathological prognosticators in oral and oropharyngeal squamous cell carcinoma.  Oral Oncol. 2006;42(3):229-239.PubMedGoogle ScholarCrossref
6.
Magnano  M, De Stefani  A, Lerda  W,  et al.  Prognostic factors of cervical lymph node metastasis in head and neck squamous cell carcinoma.  Tumori. 1997;83(6):922-926.PubMedGoogle Scholar
7.
Snow  GB, Patel  P, Leemans  CR, Tiwari  R.  Management of cervical lymph nodes in patients with head and neck cancer.  Eur Arch Otorhinolaryngol. 1992;249(4):187-194.Google ScholarCrossref
8.
Genden  EM, Ferlito  A, Bradley  PJ, Rinaldo  A, Scully  C.  Neck disease and distant metastases.  Oral Oncol. 2003;39(3):207-212.PubMedGoogle ScholarCrossref
9.
Shah  JP, Medina  JE, Shaha  AR, Schantz  SP, Marti  JR.  Cervical lymph node metastasis.  Curr Probl Surg. 1993;30(3):1-335.PubMedGoogle ScholarCrossref
10.
Woolgar  JA.  The topography of cervical lymph node metastases revisited: the histological findings in 526 sides of neck dissection from 439 previously untreated patients.  Int J Oral Maxillofac Surg. 2007;36(3):219-225.PubMedGoogle ScholarCrossref
11.
Byers  RM, Weber  RS, Andrews  T, McGill  D, Kare  R, Wolf  P.  Frequency and therapeutic implications of “skip metastases” in the neck from squamous carcinoma of the oral tongue.  Head Neck. 1997;19(1):14-19.PubMedGoogle ScholarCrossref
12.
Chaplin  JM, Morton  RP.  A prospective, longitudinal study of pain in head and neck cancer patients.  Head Neck. 1999;21(6):531-537.PubMedGoogle ScholarCrossref
13.
Taylor  RJ, Chepeha  JC, Teknos  TN,  et al.  Development and validation of the Neck Dissection Impairment Index: a quality of life measure.  Arch Otolaryngol Head Neck Surg. 2002;128(1):44-49.PubMedGoogle ScholarCrossref
14.
Laverick  S, Lowe  D, Brown  JS, Vaughan  ED, Rogers  SN.  The impact of neck dissection on health-related quality of life.  Arch Otolaryngol Head Neck Surg. 2004;130(2):149-154.PubMedGoogle ScholarCrossref
15.
Jank  S, Robatscher  P, Emshoff  R, Strobl  H, Gojer  G, Norer  B.  The diagnostic value of ultrasonography to detect occult lymph node involvement at different levels in patients with squamous cell carcinoma in the maxillofacial region.  Int J Oral Maxillofac Surg. 2003;32(1):39-42.PubMedGoogle ScholarCrossref
16.
Liao  LJ, Lo  WC, Hsu  WL, Wang  CT, Lai  MS.  Detection of cervical lymph node metastasis in head and neck cancer patients with clinically N0 neck: a meta-analysis comparing different imaging modalities.  BMC Cancer. 2012;12:236.PubMedGoogle ScholarCrossref
17.
van den Brekel  MWM, Stel  HV, Castelijns  JA,  et al.  Cervical lymph node metastasis: assessment of radiologic criteria.  Radiology. 1990;177(2):379-384.PubMedGoogle ScholarCrossref
18.
Vandenbrekel  MWM, Castelijns  JA, Croll  GA,  et al.  Magnetic resonance imaging vs palpation of cervical lymph node metastasis.  Arch Otolaryngol. 1991;117(6):666-673.Google ScholarCrossref
19.
Goerkem  M, Braun  J, Stoeckli  SJ.  Evaluation of clinical and histomorphological parameters as potential predictors of occult metastases in sentinel lymph nodes of early squamous cell carcinoma of the oral cavity.  Ann Surg Oncol. 2010;17(2):527-535.PubMedGoogle ScholarCrossref
20.
Ebrahimi  A, Gil  Z, Amit  M,  et al; International Consortium for Outcome Research (ICOR) in Head and Neck Cancer.  Primary tumor staging for oral cancer and a proposed modification incorporating depth of invasion: an international multicenter retrospective study.  JAMA Otolaryngol Head Neck Surg. 2014;140(12):1138-1148.PubMedGoogle ScholarCrossref
21.
Almangush  A, Bello  IO, Keski-Säntti  H,  et al.  Depth of invasion, tumor budding, and worst pattern of invasion: prognostic indicators in early-stage oral tongue cancer.  Head Neck. 2014;36(6):811-818.PubMedGoogle ScholarCrossref
22.
Jung  J, Cho  NH, Kim  J,  et al.  Significant invasion depth of early oral tongue cancer originated from the lateral border to predict regional metastases and prognosis.  Int J Oral Maxillofac Surg. 2009;38(6):653-660.PubMedGoogle ScholarCrossref
23.
Pentenero  M, Gandolfo  S, Carrozzo  M.  Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: a review of the literature.  Head Neck. 2005;27(12):1080-1091.PubMedGoogle ScholarCrossref
24.
O-charoenrat  P, Pillai  G, Patel  S,  et al.  Tumour thickness predicts cervical nodal metastases and survival in early oral tongue cancer.  Oral Oncol. 2003;39(4):386-390.PubMedGoogle ScholarCrossref
25.
Civantos  FJ, Zitsch  RP, Schuller  DE,  et al.  Sentinel lymph node biopsy accurately stages the regional lymph nodes for T1-T2 oral squamous cell carcinomas: results of a prospective multi-institutional trial.  J Clin Oncol. 2010;28(8):1395-1400.PubMedGoogle ScholarCrossref
26.
Shoaib  T, Soutar  DS, MacDonald  DG,  et al.  The accuracy of head and neck carcinoma sentinel lymph node biopsy in the clinically N0 neck.  Cancer. 2001;91(11):2077-2083.PubMedGoogle ScholarCrossref
27.
Taylor  RJ, Wahl  RL, Sharma  PK,  et al.  Sentinel node localization in oral cavity and oropharynx squamous cell cancer.  Arch Otolaryngol Head Neck Surg. 2001;127(8):970-974.PubMedGoogle ScholarCrossref
28.
Civantos  FJ, Moffat  FL, Goodwin  WJ.  Lymphatic mapping and sentinel lymphadenectomy for 106 head and neck lesions: contrasts between oral cavity and cutaneous malignancy.  Laryngoscope. 2006;112(3, pt 2)(suppl 109):1-15.PubMedGoogle ScholarCrossref
29.
Paleri  V, Rees  G, Arullendran  P, Shoaib  T, Krishman  S.  Sentinel node biopsy in squamous cell cancer of the oral cavity and oral pharynx: a diagnostic meta-analysis.  Head Neck. 2005;27(9):739-747.PubMedGoogle ScholarCrossref
30.
Haddadin  KJ, Soutar  DS, Oliver  RJ, Webster  MH, Robertson  AG, MacDonald  DG.  Improved survival for patients with clinically T1/T2, N0 tongue tumors undergoing a prophylactic neck dissection.  Head Neck. 1999;21(6):517-525.PubMedGoogle ScholarCrossref
31.
Ross  G, Shoaib  T, Soutar  DS,  et al.  The use of sentinel node biopsy to upstage the clinically N0 neck in head and neck cancer.  Arch Otolaryngol Head Neck Surg. 2002;128(11):1287-1291.PubMedGoogle ScholarCrossref
32.
Ross  GL, Shoaib  T.  Role of sentinel node biopsy in the management and staging of the N0 neck.  Odontology. 2005;93(1):1-6.Google ScholarCrossref
33.
Alkureishi  LW, Ross  GL, Shoaib  T,  et al.  Sentinel node biopsy in head and neck squamous cell cancer: 5-year follow-up of a European multicenter trial.  Ann Surg Oncol. 2010;17(9):2459-2464.PubMedGoogle ScholarCrossref
34.
Feinstein  AR, Wells  CK.  A clinical-severity staging system for patients with lung cancer.  Medicine (Baltimore). 1990;69(1):1-33.PubMedGoogle ScholarCrossref
35.
Gruber  S.  Clinical epidemiology: the architecture of clinical research.  Yale J Biol Med. 1986;59(1):3.Google Scholar
36.
Neely  JG, Lieu  JEC, Sequeira  SM,  et al.  Practical guide to understanding multivariable analyses, part B: conjunctive consolidation.  Otolaryngol Head Neck Surg. 2013;148(3):359-365.PubMedGoogle ScholarCrossref
37.
Sanderson  RJ, Ironside  JAD.  Squamous cell carcinomas of the head and neck.  BMJ. 2002;325(7368):822-827.PubMedGoogle ScholarCrossref
38.
Kalnins  IK, Leonard  AG, Sako  K, Razack  MS, Shedd  DP.  Correlation between prognosis and degree of lymph node involvement in carcinoma of the oral cavity.  Am J Surg. 1977;134(4):450-454.PubMedGoogle ScholarCrossref
39.
Fakih  AR, Rao  RS, Borges  AM, Patel  AR.  Elective versus therapeutic neck dissection in early carcinoma of the oral tongue.  Am J Surg. 1989;158(4):309-313.PubMedGoogle ScholarCrossref
40.
Kligerman  J, Lima  RA, Soares  JR,  et al.  Supraomohyoid neck dissection in the treatment of T1/T2 squamous cell carcinoma of oral cavity.  Am J Surg. 1994;168(5):391-394.PubMedGoogle ScholarCrossref
41.
Yuen  AP, Ho  CM, Chow  TL,  et al.  Prospective randomized study of selective neck dissection versus observation for N0 neck of early tongue carcinoma.  Head Neck. 2009;31(6):765-772.PubMedGoogle ScholarCrossref
42.
D’Cruz  AK, Vaish  R, Kapre  N,  et al; Head and Neck Disease Management Group.  Elective versus therapeutic neck dissection in node-negative oral cancer.  N Engl J Med. 2015;373(6):521-529.PubMedGoogle ScholarCrossref
43.
Fasunla  AJ, Greene  BH, Timmesfeld  N, Wiegand  S, Werner  JA, Sesterhenn  AM.  A meta-analysis of the randomized controlled trials on elective neck dissection versus therapeutic neck dissection in oral cavity cancers with clinically node-negative neck.  Oral Oncol. 2011;47(5):320-324.PubMedGoogle ScholarCrossref
44.
Vandenbrouck  C, Sancho-Garnier  H, Chassagne  D, Saravane  D, Cachin  Y, Micheau  C.  Elective versus therapeutic radical neck dissection in epidermoid carcinoma of the oral cavity: results of a randomized clinical trial.  Cancer. 1980;46(2):386-390.PubMedGoogle ScholarCrossref
45.
D’Cruz  AK, Dandekar  MR.  Elective versus therapeutic neck dissection in the clinically node negative neck in early oral cavity cancers: do we have the answer yet?  Oral Oncol. 2011;47(9):780-782.PubMedGoogle ScholarCrossref
46.
Liu  KYP, Durham  JS, Anderson  DW, Cromwell  I, Poh  CF. Dissect or not dissect on N0 oral cancer patient's necks: impact on resource utilization. Paper presented at: 3rd Annual Scientific Meeting of the Terry Fox Research Institute; May 11, 2012; Vancouver, BC.
47.
Roland  NJ, Caslin  AW, Nash  J, Stell  PM.  Value of grading squamous cell carcinoma of the head and neck.  Head Neck. 1992;14(3):224-229.PubMedGoogle ScholarCrossref
48.
Bryne  M, Nielsen  K, Koppang  HS, Dabelsteen  E.  Reproducibility of two malignancy grading systems with reportedly prognostic value for oral cancer patients.  J Oral Pathol Med. 1991;20(8):369-372.Google ScholarCrossref
49.
Balasubramanian  D, Ebrahimi  A, Gupta  R,  et al.  Tumour thickness as a predictor of nodal metastases in oral cancer: comparison between tongue and floor of mouth subsites.  Oral Oncol. 2014;50(12):1165-1168.PubMedGoogle ScholarCrossref
50.
O’Brien  CJ, Traynor  SJ, McNeil  E, McMahon  JD, Chaplin  JM.  The use of clinical criteria alone in the management of the clinically negative neck among patients with squamous cell carcinoma of the oral cavity and oropharynx.  Arch Otolaryngol Head Neck Surg. 2000;126(3):360-365.PubMedGoogle ScholarCrossref
51.
Mishra  RC, Parida  G, Mishra  TK, Mohanty  S.  Tumour thickness and relationship to locoregional failure in cancer of the buccal mucosa.  Eur J Surg Oncol. 1999;25(2):186-189.PubMedGoogle ScholarCrossref
52.
Hanahan  D, Weinberg  RA.  Hallmarks of cancer: the next generation.  Cell. 2011;144(5):646-674.PubMedGoogle ScholarCrossref
53.
Xu  Y, Lefèvre  M, Périé  S,  et al.  Clinical significance of micrometastases detection in lymph nodes from head and neck squamous cell carcinoma.  Otolaryngol Head Neck Surg. 2008;139(3):436-441.PubMedGoogle ScholarCrossref
54.
Woolgar  JA, Vaughan  ED, Scott  J, Brown  JS.  Pathological findings in clinically false-negative and false-positive neck dissections for oral carcinoma.  Ann R Coll Surg Engl. 1994;76(4):237-244.PubMedGoogle Scholar
55.
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.  Otolaryng Head Neck. 2015;153(3):8.PubMedGoogle Scholar
56.
Lawrence  MS, Sougnez  C, Lichtenstein  L,  et al; Cancer Genome Atlas Network.  Comprehensive genomic characterization of head and neck squamous cell carcinomas.  Nature. 2015;517(7536):576-582.PubMedGoogle ScholarCrossref
57.
Roepman  P, Kemmeren  P, Wessels  LFA, Slootweg  PJ, Holstege  FCP.  Multiple robust signatures for detecting lymph node metastasis in head and neck cancer.  Cancer Res. 2006;66(4):2361-2366.PubMedGoogle ScholarCrossref
58.
Poh  CF, Durham  JS, Brasher  PM,  et al.  Canadian Optically-Guided Approach for Oral Lesions Surgical (COOLS) trial: study protocol for a randomized controlled trial.  BMC Cancer. 2011;11:462.PubMedGoogle ScholarCrossref
Original Investigation
November 2016

Nodal Disease Burden for Early-Stage Oral Cancer

Author Affiliations
  • 1Department of Oral Medical Biological Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, Canada
  • 2Department of Integrative Oncology, BC Cancer Research Centre, Vancouver, British Columbia, Canada
  • 3Division of Otolaryngology–Head and Neck Surgery, Department of Oral Biological and Medical Science, University of British Columbia, Vancouver, Canada
  • 4Department of Radiation Oncology, BC Cancer Agency, Vancouver Center, Vancouver, British Columbia, Canada
  • 5Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
JAMA Otolaryngol Head Neck Surg. 2016;142(11):1111-1119. doi:10.1001/jamaoto.2016.2241
Key Points

Question  Does prophylactic neck dissection provide a survival advantage in patients with clinically node-negative (cN0) oral cancer?

Findings  In this population-based retrospective study, patients who received prophylactic neck treatment had no survival advantage compared with those who received local excision only, and a subgroup of patients at who developed neck disease at follow-up received salvage neck treatment and had the worst survival. Tumor depth of invasion of at least 4 mm was significant but had poor sensitivity and specificity in association with nodal disease.

Meaning  New objective markers are urgently needed to identify high-risk patients with cN0 oral squamous cell carcinoma who may benefit from prophylactic neck treatment.

Abstract

Importance  Nodal disease has a significant effect on survival of patients with oral squamous cell carcinoma (OSCC). The decision for elective neck dissection for clinically node-negative (cN0) disease remains elusive.

Objectives  To determine the efficacy of prophylactic neck treatment and to assess the value of commonly used clinicopathologic factors associated with nodal disease for early-stage OSCC.

Design, Setting, and Participants  This retrospective study from a population-based cancer registry included patients diagnosed as having OSCC from January 11, 2001, to December 24, 2007, who were identified from the British Columbia Cancer Agency Registry. Comprehensive clinicopathologic data, treatment information, and time to outcome were collected. Five-year overall survival, disease-specific survival, and cumulative incidence of regional failure (RF) were analyzed. Receiver operating characteristic curve analysis with sensitivity and specificity was used to determine the association of these covariates with RF during follow-up. Data were analyzed from January 16 to June 30, 2015.

Interventions  Follow-up of patients with cN0 OSCC with or without prophylactic neck treatment (elective neck dissection [END] and or radiotherapy).

Main Outcomes and Measures  Patient demographic characteristics, clinicopathologic data, treatment data, and time from the initial surgery to last follow-up, the development of RF, or death due to oral cancer or other causes.

Results  Of the 469 patients with cN0 primary OSCC who underwent intent-to-cure surgery for the intraoral lesion, 447 received local excision (LE) for the primary tumor (256 men [57.3%] and 191 women [42.7%]; mean [SD] age, 63.3 [14.7] years). Patients who received prophylactic treatment of the neck (n = 125) compared with LE only (n = 322) had no survival advantage. The estimated 5-year overall and disease-specific survival rates were 61.9% (95% CI, 56.5%-67.8%) and 80.8% (95% CI, 76.1%-85.6%), respectively, for the LE-only group; 54.4% (95% CI, 45.9%-64.5%) and 73.1% (95% CI, 65%-82.3%), respectively, for the LE + END ± radiotherapy group; and 61.7% (95% CI, 52.3%-72.8%) and 80.3% (95% CI, 72%-89.4%), respectively, for the LE + END group. Among the patients with cN0 disease receiving LE only, 89 (27.6%; 95% CI, 23%-33%) developed RF at a median time of 10.8 months, and 71 of the RFs (79.8%) developed within 30 months. Tumor depth of invasion of at least 4 mm and tumor grade of 2 or 3 showed an association with RF but had poor sensitivity and specificity.

Conclusions and Relevance  Commonly used pathologic factors to decide neck dissection for cN0 OSCC are not effective and can cause overtreatment or undertreatment. The need for identification of new objective approaches for risk assessment of RF is urgent.

Introduction

Each year, 274 000 new cases of oral squamous cell carcinoma (OSCC) occur, accounting for 145 000 deaths worldwide.1 The reported 5-year survival rates range from 30% to 60% and are among the worst for all cancer types. Despite continued advances in therapeutic techniques, the prognosis of OSCC has not changed significantly during the past 50 years.2 The presence of neck node metastasis at presentation or during follow-up is the most important prognostic factor in assessing patient survival.3-11

Patients with clinically evident neck metastasis (cN+) commonly undergo neck dissection with or without adjuvant radiotherapy (RT), whereas patients with clinically node-negative (cN0) disease may be offered prophylactic neck dissection to prevent regional failure (RF) and associated decreased survival. However, the sequelae of surgery may result in a significant reduction in patients’ well-being and quality of life owing to scarring, depression, or other health indicators that are not often captured by survival analysis.12-14 Therefore, correct identification of patients with the highest risk for the development of RF is critical to minimize unnecessary morbidity.

Clinicians rely on a combination of clinical, radiological, and pathologic features to provide a management plan for each patient. Despite advances in medical imaging, including high-resolution computed tomographic and magnetic resonance imaging scans and functional positron emission tomographic imaging, a significant amount of occult neck disease cannot be identified by these methods.5,15-18 Therefore, alternative predictors of nodal disease have been investigated, such as tumor depth of invasion (DOI) and sentinel lymph node biopsy, to help identify those patients with cN0 disease at increased risk for nodal disease. A greater DOI has been associated with an increased risk for nodal metastases, but the value of DOI to rationalize the potential morbidity associated with elective neck dissection (END) remains controversial.19-24 Sentinel lymph node biopsy has been reported to have high positive and negative predictive values for occult nodal metastasis.25-33 However, the procedure has not gained widespread use for OSCC because it requires surgeons and pathologists experienced in the technique and results in prolonged surgery time with increased treatment cost.32 Thus, identification of decisive variables associated with nodal disease remains elusive, and the decision for treatment of the neck in cN0 disease rests on the surgeon’s judgment and patient’s circumstances.

This study retrospectively describes the incidence of nodal disease among patients with cN0 OSCC in British Columbia, Canada. We investigate (1) the efficacy of prophylactic neck treatment for early-stage OSCC, (2) the frequency and timing of the development of RF at follow-up, and (3) the efficacy of commonly used clinicopathologic factors associated with RF for early-stage OSCC.

Methods
Patients, Treatment, and Outcomes

Data of patients diagnosed as having OSCC from January 11, 2001, to December 24, 2007, were retrospectively retrieved from the British Columbia Cancer Agency Registry. Data were analyzed from January 16 to June 30, 2015. Eligible OSCC included anatomical sites represented by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes C02.0 to C06.9, all tumor stages, and cN0 status at the time of initial disease presentation. We excluded patients whose anatomical sites were the base of tongue, tonsillar area, and lips. Information on age, sex, and tumor anatomical sites were extracted directly from the Registry. Medical record review was performed to collect history of tobacco use, initial clinical tumor stage, treatment types, tumor grade, and tumor DOI.

Patients with cN0 disease who underwent local excision (LE) with curative intent, with or without neck dissection, were included in the study. Elective neck dissection was defined as neck dissection performed at the time of LE of the primary lesion or after the pathologic evaluation of the primary tumor. Outcome events included in this study were (1) 5-year overall survival (OS), calculated from the time of initial treatment to the date of death due to any cause or the last known date alive; (2) 5-year disease-specific survival (DSS), calculated from the time of initial treatment to the date of death due to oral cancer or the last known date alive; and (3) 5-year cumulative incidence rate of RF, calculated from the time of initial treatment to the development of pathologically proven squamous cell carcinoma in regional neck lymph nodes.

This study was approved by the institutional review board of the University of British Columbia, who waived the need for informed consent for this retrospective registry review.

Statistical Analysis

Statistical analysis was performed with R software (version 3.2.3; https://cran.r-project.org/bin/windows/base/old/3.2.3/). Patient demographic, clinical, and tumor characteristics were summarized in descriptive absolute and relative frequencies and as means with SDs. Categorical variables were compared using the χ2 or the Fisher exact test. Continuous variables were compared using the 2-tailed t test.

We used Kaplan-Meier survival analysis to estimate the proportion of survival with log-rank tests for between-group comparison. Cumulative incidence rate of RF was calculated after adjusting for death due to any cause, a competing risk factor. We used the Cox proportional hazards regression analysis to estimate the effect of variables (age, sex, history of tobacco use, lesion site, tumor size, presence of nodal disease, or initial treatment types) on survival. Univariate and multivariate logistic regression analyses were performed to ascertain the effects of these variables on the likelihood that patients with cN0 disease developed RF. Receiver operating characteristics analysis was performed to determine the association of DOI with true RF vs true RF-free outcomes in patients with cN0 disease. Tests were 2-tailed, with P < .05 considered significant.

Results
Patients

We identified 3054 eligible patients from the British Columbia Cancer Agency Registry. Among them, 861 patients (28.2%) had primary OSCC, of whom 617 (71.7%) had cN0 disease. Figure 1 illustrates the study population with nodal status at the initial presentation, initial treatment types, and nodal status at the initial treatment and during follow-up.

For the 447 patients with cN0 disease who received LE for the primary tumor and constituted the study population (256 men [57.3%] and 191 women [42.7%]; mean [SD] age, 63.3 [14.7] years), 322 (72%) received LE only and 125 (28%) received LE with additional prophylactic neck treatment, including END with (n = 25) or without (n = 100) adjuvant RT (Figure 1). Of the 469 patients, 22 (4.7%) received radiotherapy for positive margins or adjuvant intent after LE. This may confound the outcome of nodal disease. Thus, they were excluded from the downstream analysis. Among the 125 patients, 15 (12%; 95% CI, 6%-18%) had pathologically positive nodes (pN+) at the time of END, whereas 12 (9.6%; 95% CI, 4.3%-15%) developed RF during follow-up. For 322 patients with cN0 disease who underwent LE only, 89 (27.6%; 95% CI, 23%-33%) developed RF at follow-up.

Efficacy of Prophylactic Neck Treatment in cN0 Patients

To examine whether survival was improved for patients with prophylactic neck treatment, we compared the LE-only group (n = 322) with the prophylactic treatment group (LE + END ± RT) (n = 125) or the LE + END group (no RT) (n = 100) (eTable1 in the Supplement). The estimated 5-year OS and DSS rates were 61.9% (95% CI, 56.5%-67.8%) and 80.8% (95% CI, 76.1%-85.6%), respectively, for the LE-only group; 54.4% (95% CI, 45.9%-64.5%) and 73.1% (95% CI, 65%-82.3%), respectively, for the LE + END ± RT group; and 61.7% (95% CI, 52.3%-72.8%) and 80.3% (95% CI, 72%-89.4%), respectively, for the LE + END group. Compared with the LE-only group, the LE + END ± RT group showed hazard ratios of 1.3 (95% CI, 0.9-1.8) and 1.4 (95% CI, 0.9-2.3) in 5-year OS and DSS rates, respectively. Similarly, the LE + END group showed hazard ratios of 0.99 (95% CI, 0.7-1.7) and 1.0 (95% CI, 0.7-1.5) in 5-year OS and DSS rates, respectively. We found no statistical difference between the LE-only and the LE + END ± RT groups in 5-year OS and DSS rates (Figure 2 and eTable2 in the Supplement).

Time to RF in cN0 Disease

To avoid any confounding factors caused by the delivery of prophylactic neck treatment, a subset of patients with cN0 disease who received LE only (n = 322) were included in the examination of the incidence of RF during follow-up and its possible predictors. Patient demographics and clinicopathologic characteristics are summarized in the Table. For convenience, we used cN0→cN0 to represent the group of patients with cN0 disease throughout follow-up and cN0→pN+ to represent the group of patients with cN0 disease at the initial presentation and pN+ disease during follow-up. Among the 89 patients with cN0→pN+, the median time from LE to pN+ disease was less than 1 year (mean, 10.8 months; 95% CI, 9.5-15.1 months), and 71 (79.8%) of them developed pN+ disease within 30 months (Figure 3). In addition, the 5-year DSS was significantly reduced in this group compared with the cN0→cN0 group (32 patients [56.6%] vs 122 patients [91%]).

Does Invasion Depth of at Least 4 mm Justify Neck Dissections?

Using univariate logistic regression analysis, we observed that high-risk lesion sites (tongue and the floor of the mouth), tumor grade of 2 or 3, and DOI of at least 4 mm were associated with RF. In multivariate analysis, only tumor grade 2 or 3 and DOI of at least 4 mm were independent factors. Compared with a DOI of less than 4 mm, patients with a DOI of at least 4 mm showed an odds ratio of 2.0 (95% CI, 1.2-3.6) in developing RF (eTable3 in the Supplement).

When assessing the association of the DOI with RF, the receiver operating characteristics curve analysis showed an area under the curve of 63.2% (95% CI, 55.8%-70.6%). Setting a DOI of 4 mm as the cutoff resulted in poor sensitivity, specificity, and positive and negative predictive values (54.2%, 67.3%, 45%, and 74.8%, respectively). Tumor grade of 2 or 3 had a better sensitivity of 72.3% but poorer specificity of 48.8%. For a high-risk lesion site, sensitivity and specificity were 86.7% and 26.8%, respectively (eTable 4 in the Supplement).

Using the conjunctive consolidation technique34-36 for various combinations of categories of DOI (4-mm cutoffs) and tumor grades, we have identified 4 new categories with gradients of proportion of pN+ at follow-up from 15.9% to 60%. Compared with the group with a DOI of less than 4 mm and grade 1, the odds ratios were 2.0 (95% CI, 1.0-4.1) for the group with DOI of less than 4 mm and grade 2 or 3 or a DOI of at least 4 mm and grade 1; 4.3 (95% CI, 2.0-9.5) for the group with a DOI of at least 4 mm and grade 2; and 8.0 (95% CI, 2.0-35.1) for the group with a DOI of at least 4 mm and grade 3. For multivariate analysis, only the group with a DOI of at least 4 mm and grade 2 was selected, showing low sensitivity (64.3%) and specificity (18%) (eTable 3 in the Supplement).

We further examined the proportion of patients with cN0→cN0 and cN0→pN+ who would be overtreated or undertreated at their corresponding DOIs (Figure 4). We observed that if an END was performed on all patients who had a DOI of at least 4 mm, only 45 (45%) would have occult metastatic neck disease treated, and 38 (25.2%) would have occult neck disease not addressed as the primary tumor had a DOI of less than 4 mm.

Discussion

The presence of regional nodal disease is indeed a burden for patients with OSCC. In our study cohort, nearly half of the patients (363 of 847 [42.9%]) had nodal disease at the time of initial presentation (n = 244), at the time of END (n = 15), or within the 5-year follow-up (n = 104). This finding echoes previously published data from other groups.4,37,38 The present study presents, to our knowledge, the largest population-based cohort of patients with cN0 disease to help address the efficacy of prophylactic neck treatment and to examine the natural history of the disease burden without neck treatment.

Several randomized clinical trials have suggested benefits from elective or prophylactic neck treatment for cN0 disease.39-42 A Cochrane meta-analysis,43 including 4 small sample-size randomized clinical trials with a pooled total of 283 patients, stated that END reduced the risk for disease-specific death by approximately 40%. The authors admitted that the observed benefits of END in patients with cN0 disease were mostly contributed from older studies. Although the advancement in imaging technology improved the early detection of clinically occult disease at follow-up and the success of salvage neck treatment, 1 newer study41 did not observe the benefits in DSS between END and no-END groups. This observation concurred with our finding of a lack of significant improvement in survival with the deliverance of prophylactic neck treatment.

The most recently published randomized clinical trial investigating the efficacy of END42 enrolled 500 patients with early-stage (T1 and T2) OSCC and suggested a significant improvement in OS and disease-free survival in patients. Notably, the report was premature, with 25% of patients having less than 16 months of follow-up. In addition, disease-free survival, defined as the interval from the date of randomization to the first documented evidence of any disease or death due to any cause, is clinically less meaningful than DSS and can lead to false conclusions. For example, for patients in the control group who developed nodal disease at follow-up, disease-free survival does not capture the effect on survival because the first incidence of nodal disease was counted as an event before death could happen. For those in the experimental group (ie, END), the high incidence of clinically occult disease at the time of END (24%) was not counted as an event until the reoccurrence of nodal disease, with significant time-to-event delay in this scenario. Therefore, the statistically significant difference in disease-free survival may inflate the benefits of the experimental group. Clinical equipoise remains in this area.40,44,45

The presence of nodal disease at the time of surgery or at follow-up is a significant independent prognostic factor on survival. With just more than one-fourth of patients with cN0 disease (89 [27.6%]) developing nodal diseases during follow-up, performing prophylactic neck treatment would result in overtreating 233 patients (72.4%) with cN0 disease. Unnecessary treatment may involve significant cost and morbidity. In a previous report on resource use in surgical procedures for early-stage oral cancer,46 LE only required significantly shorter operative time (mean [SD], 4.3 [2.2] vs 1.0 [0.3] hours) and shorter postoperative hospitalization (36 vs 4 hours) compared with procedures that included neck dissection.

With the combination of DOI of at least 4 mm and tumor grade 3, our data showed a significantly high odds ratio. Although this combination seemed to have high sensitivity (92.9%), owing to the low case number (n = 10), the specificity was minimal (2%, meaning high false-negative rates) and may not be clinically useful. In addition, the decision of tumor grade has its inherited problems, including sampling bias, intrinsic interobserver variability, subjectivity, and low specificity (most cases were grade 2), making it an unreliable prognostic factor.47,48 Preoperative means to measure a true DOI are only approximations at best, and surgical samples are formalin fixed and, in most cases, only available after tumor excision. Therefore, DOI, like tumor grade, cannot be used as a real-time clinical decision-making aid for preoperative or intraoperative planning. In addition, the DOI threshold for nodal metastatic risk may vary across oral cavity subsites.49-51 Without level 1 evidence, the use of 4-mm DOI as a single indicator to decide the need for END should be of paramount caution. In this scenario, any additional treatment for patients who will never develop nodal disease would result in increased hospitalization, associated costs, patient morbidity, and patient convalescence.

We also observed RF in patients with smaller tumors, whereas patients with thicker tumors remained free of nodal disease (Figure 4). This observation evidently shifts the paradigm that smaller tumors are less aggressive and patients are at lower risk for developing nodal disease. Our data also showed near-plateau numbers of undertreatment and overtreatment at various DOI cutoffs (Figure 4), further indicating the limitation of DOI alone in capturing and justifying neck dissection. The need for objective real-time biomarkers to predict nodal disease for treatment planning at initial diagnostic biopsy is urgent.

Cancer metastasis to regional lymph nodes has been recognized as one of the hallmarks of carcinogenesis and involves a complicated, multistep process.52 Because we found that approximately 80% of patients with cN0 disease who developed RF did so within 30 months after initial LE in our cohort, we hypothesize that the tumors with nodal involvement are molecularly different from those without. Moreover, among those with cN0 disease who underwent END, we found a subset of patients with disease refractory to prophylactic neck treatment as evidenced by 18 patients, including 6 of 15 patients with pN+ disease (40%; 95% CI, 15%-65%) and 12 of 110 patients with pN0 disease (10.9%; 95% CI, 5%- 17%) at the time of neck dissection who developed pN+ disease during follow-up despite having received neck treatment. This observation, combined with the unreliability of DOI, may reflect the phenomenon of skip metastasis11 or suggest that subgroups within OSCC are biologically and behaviorally different. Other explanations, such as the presence of micrometastases not identified in the pathologic specimen53,54 or of insufficient nodal yield at the first surgery,55 are also possible. Ongoing efforts from our group and others using advanced molecular and optical technologies may provide promising leads for better understanding.56,57 If we can identify a higher-risk cohort of patients, then END should confer a survival advantage over “wait and treat,” but if END is practiced in a less discriminating fashion, no such survival advantage is demonstrated, as discussed earlier.

Several inherent limitations of this retrospective study include potential selection bias and a lack of consensus as to when an END was performed. Information on alcohol use or comorbidities that are potential risk factors for survival were missing from most of the patient medical records and are not available for analysis. However, through the funding support from the Terry Fox Research Institute, the COOLS (Canadian Optically-guided Approach for Oral Lesions Surgical) study, a pan-Canadian phase 3 randomized clinical trial for early-stage oral cancer, has completed the accrual of 400 surgically treated patients who are currently being observed.58 The results from this trial will be able to confirm findings with direct and indirect cost reports in the near future. In addition, fresh-frozen plasma samples collected in this trial, along with comprehensive annotation and long-term follow-up information, would be submitted for next-generation molecular studies and should definitely enhance our understanding of the biology and clinical behavior of this disease.

Conclusions

Prophylactic neck treatment may not improve patient survival, and although reliance on a DOI of at least 4 mm is associated with a higher incidence of RF, it has poor sensitivity and specificity for nodal involvement among patients with early-stage cN0 disease. Because these current standards of care are unreliable, the need to identify other effective standards, perhaps biomarkers with greater specificity and sensitivity in determining a high-risk group of nodal disease, is alarming. Only after identification of these other effective standards will we be able to accurately investigate whether END could in fact confer a survival advantage.

Back to top
Article Information

Corresponding Author: Catherine F. Poh, DDS, PhD, Department of Oral Medical and Biological Sciences, Faculty of Dentistry, University of British Columbia, 2199 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada (cpoh@dentistry.ubc.ca).

Accepted for Publication: June 24, 2016.

Published Online: August 25, 2016. doi:10.1001/jamaoto.2016.2241

Author Contributions: Ms Liu and Dr Poh had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Liu, Prisman, Poh.

Acquisition, analysis, or interpretation of data: Liu, Durham, Wu, Anderson, Poh.

Drafting of the manuscript: Liu, Durham, Prisman, Poh.

Critical revision of the manuscript for important intellectual content: Liu, Wu, Anderson, Poh.

Statistical analysis: Liu, Poh.

Obtained funding: Poh.

Administrative, technical, or material support: Liu, Durham, Poh.

Study supervision: Durham, Wu, Prisman, Poh.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: The study was supported by grant 20336 from the Canadian Cancer Society Research Institute, grant 2009-24 from the Terry Fox Research Institute, and the BC Cancer Foundation.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Jack J. Lee, DDS, PhD, Anderson Cancer Institute, provided guidance on data analysis. Tony Han, BS, provided editorial assistance. Both received compensation for their roles.

References
1.
Johnson  NW, Jayasekara  P, Amarasinghe  AA.  Squamous cell carcinoma and precursor lesions of the oral cavity: epidemiology and aetiology.  Periodontol 2000. 2011;57(1):19-37.PubMedGoogle ScholarCrossref
2.
Huang  TY, Hsu  LP, Wen  YH,  et al.  Predictors of locoregional recurrence in early stage oral cavity cancer with free surgical margins.  Oral Oncol. 2010;46(1):49-55.PubMedGoogle ScholarCrossref
3.
Ho  CM, Lam  KH, Wei  WI, Lau  SK, Lam  LK.  Occult lymph node metastasis in small oral tongue cancers.  Head Neck. 1992;14(5):359-363.PubMedGoogle ScholarCrossref
4.
Le Tourneau  C, Velten  M, Jung  GM, Bronner  G, Flesch  H, Borel  C.  Prognostic indicators for survival in head and neck squamous cell carcinomas: analysis of a series of 621 cases.  Head Neck. 2005;27(9):801-808.PubMedGoogle ScholarCrossref
5.
Woolgar  JA.  Histopathological prognosticators in oral and oropharyngeal squamous cell carcinoma.  Oral Oncol. 2006;42(3):229-239.PubMedGoogle ScholarCrossref
6.
Magnano  M, De Stefani  A, Lerda  W,  et al.  Prognostic factors of cervical lymph node metastasis in head and neck squamous cell carcinoma.  Tumori. 1997;83(6):922-926.PubMedGoogle Scholar
7.
Snow  GB, Patel  P, Leemans  CR, Tiwari  R.  Management of cervical lymph nodes in patients with head and neck cancer.  Eur Arch Otorhinolaryngol. 1992;249(4):187-194.Google ScholarCrossref
8.
Genden  EM, Ferlito  A, Bradley  PJ, Rinaldo  A, Scully  C.  Neck disease and distant metastases.  Oral Oncol. 2003;39(3):207-212.PubMedGoogle ScholarCrossref
9.
Shah  JP, Medina  JE, Shaha  AR, Schantz  SP, Marti  JR.  Cervical lymph node metastasis.  Curr Probl Surg. 1993;30(3):1-335.PubMedGoogle ScholarCrossref
10.
Woolgar  JA.  The topography of cervical lymph node metastases revisited: the histological findings in 526 sides of neck dissection from 439 previously untreated patients.  Int J Oral Maxillofac Surg. 2007;36(3):219-225.PubMedGoogle ScholarCrossref
11.
Byers  RM, Weber  RS, Andrews  T, McGill  D, Kare  R, Wolf  P.  Frequency and therapeutic implications of “skip metastases” in the neck from squamous carcinoma of the oral tongue.  Head Neck. 1997;19(1):14-19.PubMedGoogle ScholarCrossref
12.
Chaplin  JM, Morton  RP.  A prospective, longitudinal study of pain in head and neck cancer patients.  Head Neck. 1999;21(6):531-537.PubMedGoogle ScholarCrossref
13.
Taylor  RJ, Chepeha  JC, Teknos  TN,  et al.  Development and validation of the Neck Dissection Impairment Index: a quality of life measure.  Arch Otolaryngol Head Neck Surg. 2002;128(1):44-49.PubMedGoogle ScholarCrossref
14.
Laverick  S, Lowe  D, Brown  JS, Vaughan  ED, Rogers  SN.  The impact of neck dissection on health-related quality of life.  Arch Otolaryngol Head Neck Surg. 2004;130(2):149-154.PubMedGoogle ScholarCrossref
15.
Jank  S, Robatscher  P, Emshoff  R, Strobl  H, Gojer  G, Norer  B.  The diagnostic value of ultrasonography to detect occult lymph node involvement at different levels in patients with squamous cell carcinoma in the maxillofacial region.  Int J Oral Maxillofac Surg. 2003;32(1):39-42.PubMedGoogle ScholarCrossref
16.
Liao  LJ, Lo  WC, Hsu  WL, Wang  CT, Lai  MS.  Detection of cervical lymph node metastasis in head and neck cancer patients with clinically N0 neck: a meta-analysis comparing different imaging modalities.  BMC Cancer. 2012;12:236.PubMedGoogle ScholarCrossref
17.
van den Brekel  MWM, Stel  HV, Castelijns  JA,  et al.  Cervical lymph node metastasis: assessment of radiologic criteria.  Radiology. 1990;177(2):379-384.PubMedGoogle ScholarCrossref
18.
Vandenbrekel  MWM, Castelijns  JA, Croll  GA,  et al.  Magnetic resonance imaging vs palpation of cervical lymph node metastasis.  Arch Otolaryngol. 1991;117(6):666-673.Google ScholarCrossref
19.
Goerkem  M, Braun  J, Stoeckli  SJ.  Evaluation of clinical and histomorphological parameters as potential predictors of occult metastases in sentinel lymph nodes of early squamous cell carcinoma of the oral cavity.  Ann Surg Oncol. 2010;17(2):527-535.PubMedGoogle ScholarCrossref
20.
Ebrahimi  A, Gil  Z, Amit  M,  et al; International Consortium for Outcome Research (ICOR) in Head and Neck Cancer.  Primary tumor staging for oral cancer and a proposed modification incorporating depth of invasion: an international multicenter retrospective study.  JAMA Otolaryngol Head Neck Surg. 2014;140(12):1138-1148.PubMedGoogle ScholarCrossref
21.
Almangush  A, Bello  IO, Keski-Säntti  H,  et al.  Depth of invasion, tumor budding, and worst pattern of invasion: prognostic indicators in early-stage oral tongue cancer.  Head Neck. 2014;36(6):811-818.PubMedGoogle ScholarCrossref
22.
Jung  J, Cho  NH, Kim  J,  et al.  Significant invasion depth of early oral tongue cancer originated from the lateral border to predict regional metastases and prognosis.  Int J Oral Maxillofac Surg. 2009;38(6):653-660.PubMedGoogle ScholarCrossref
23.
Pentenero  M, Gandolfo  S, Carrozzo  M.  Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: a review of the literature.  Head Neck. 2005;27(12):1080-1091.PubMedGoogle ScholarCrossref
24.
O-charoenrat  P, Pillai  G, Patel  S,  et al.  Tumour thickness predicts cervical nodal metastases and survival in early oral tongue cancer.  Oral Oncol. 2003;39(4):386-390.PubMedGoogle ScholarCrossref
25.
Civantos  FJ, Zitsch  RP, Schuller  DE,  et al.  Sentinel lymph node biopsy accurately stages the regional lymph nodes for T1-T2 oral squamous cell carcinomas: results of a prospective multi-institutional trial.  J Clin Oncol. 2010;28(8):1395-1400.PubMedGoogle ScholarCrossref
26.
Shoaib  T, Soutar  DS, MacDonald  DG,  et al.  The accuracy of head and neck carcinoma sentinel lymph node biopsy in the clinically N0 neck.  Cancer. 2001;91(11):2077-2083.PubMedGoogle ScholarCrossref
27.
Taylor  RJ, Wahl  RL, Sharma  PK,  et al.  Sentinel node localization in oral cavity and oropharynx squamous cell cancer.  Arch Otolaryngol Head Neck Surg. 2001;127(8):970-974.PubMedGoogle ScholarCrossref
28.
Civantos  FJ, Moffat  FL, Goodwin  WJ.  Lymphatic mapping and sentinel lymphadenectomy for 106 head and neck lesions: contrasts between oral cavity and cutaneous malignancy.  Laryngoscope. 2006;112(3, pt 2)(suppl 109):1-15.PubMedGoogle ScholarCrossref
29.
Paleri  V, Rees  G, Arullendran  P, Shoaib  T, Krishman  S.  Sentinel node biopsy in squamous cell cancer of the oral cavity and oral pharynx: a diagnostic meta-analysis.  Head Neck. 2005;27(9):739-747.PubMedGoogle ScholarCrossref
30.
Haddadin  KJ, Soutar  DS, Oliver  RJ, Webster  MH, Robertson  AG, MacDonald  DG.  Improved survival for patients with clinically T1/T2, N0 tongue tumors undergoing a prophylactic neck dissection.  Head Neck. 1999;21(6):517-525.PubMedGoogle ScholarCrossref
31.
Ross  G, Shoaib  T, Soutar  DS,  et al.  The use of sentinel node biopsy to upstage the clinically N0 neck in head and neck cancer.  Arch Otolaryngol Head Neck Surg. 2002;128(11):1287-1291.PubMedGoogle ScholarCrossref
32.
Ross  GL, Shoaib  T.  Role of sentinel node biopsy in the management and staging of the N0 neck.  Odontology. 2005;93(1):1-6.Google ScholarCrossref
33.
Alkureishi  LW, Ross  GL, Shoaib  T,  et al.  Sentinel node biopsy in head and neck squamous cell cancer: 5-year follow-up of a European multicenter trial.  Ann Surg Oncol. 2010;17(9):2459-2464.PubMedGoogle ScholarCrossref
34.
Feinstein  AR, Wells  CK.  A clinical-severity staging system for patients with lung cancer.  Medicine (Baltimore). 1990;69(1):1-33.PubMedGoogle ScholarCrossref
35.
Gruber  S.  Clinical epidemiology: the architecture of clinical research.  Yale J Biol Med. 1986;59(1):3.Google Scholar
36.
Neely  JG, Lieu  JEC, Sequeira  SM,  et al.  Practical guide to understanding multivariable analyses, part B: conjunctive consolidation.  Otolaryngol Head Neck Surg. 2013;148(3):359-365.PubMedGoogle ScholarCrossref
37.
Sanderson  RJ, Ironside  JAD.  Squamous cell carcinomas of the head and neck.  BMJ. 2002;325(7368):822-827.PubMedGoogle ScholarCrossref
38.
Kalnins  IK, Leonard  AG, Sako  K, Razack  MS, Shedd  DP.  Correlation between prognosis and degree of lymph node involvement in carcinoma of the oral cavity.  Am J Surg. 1977;134(4):450-454.PubMedGoogle ScholarCrossref
39.
Fakih  AR, Rao  RS, Borges  AM, Patel  AR.  Elective versus therapeutic neck dissection in early carcinoma of the oral tongue.  Am J Surg. 1989;158(4):309-313.PubMedGoogle ScholarCrossref
40.
Kligerman  J, Lima  RA, Soares  JR,  et al.  Supraomohyoid neck dissection in the treatment of T1/T2 squamous cell carcinoma of oral cavity.  Am J Surg. 1994;168(5):391-394.PubMedGoogle ScholarCrossref
41.
Yuen  AP, Ho  CM, Chow  TL,  et al.  Prospective randomized study of selective neck dissection versus observation for N0 neck of early tongue carcinoma.  Head Neck. 2009;31(6):765-772.PubMedGoogle ScholarCrossref
42.
D’Cruz  AK, Vaish  R, Kapre  N,  et al; Head and Neck Disease Management Group.  Elective versus therapeutic neck dissection in node-negative oral cancer.  N Engl J Med. 2015;373(6):521-529.PubMedGoogle ScholarCrossref
43.
Fasunla  AJ, Greene  BH, Timmesfeld  N, Wiegand  S, Werner  JA, Sesterhenn  AM.  A meta-analysis of the randomized controlled trials on elective neck dissection versus therapeutic neck dissection in oral cavity cancers with clinically node-negative neck.  Oral Oncol. 2011;47(5):320-324.PubMedGoogle ScholarCrossref
44.
Vandenbrouck  C, Sancho-Garnier  H, Chassagne  D, Saravane  D, Cachin  Y, Micheau  C.  Elective versus therapeutic radical neck dissection in epidermoid carcinoma of the oral cavity: results of a randomized clinical trial.  Cancer. 1980;46(2):386-390.PubMedGoogle ScholarCrossref
45.
D’Cruz  AK, Dandekar  MR.  Elective versus therapeutic neck dissection in the clinically node negative neck in early oral cavity cancers: do we have the answer yet?  Oral Oncol. 2011;47(9):780-782.PubMedGoogle ScholarCrossref
46.
Liu  KYP, Durham  JS, Anderson  DW, Cromwell  I, Poh  CF. Dissect or not dissect on N0 oral cancer patient's necks: impact on resource utilization. Paper presented at: 3rd Annual Scientific Meeting of the Terry Fox Research Institute; May 11, 2012; Vancouver, BC.
47.
Roland  NJ, Caslin  AW, Nash  J, Stell  PM.  Value of grading squamous cell carcinoma of the head and neck.  Head Neck. 1992;14(3):224-229.PubMedGoogle ScholarCrossref
48.
Bryne  M, Nielsen  K, Koppang  HS, Dabelsteen  E.  Reproducibility of two malignancy grading systems with reportedly prognostic value for oral cancer patients.  J Oral Pathol Med. 1991;20(8):369-372.Google ScholarCrossref
49.
Balasubramanian  D, Ebrahimi  A, Gupta  R,  et al.  Tumour thickness as a predictor of nodal metastases in oral cancer: comparison between tongue and floor of mouth subsites.  Oral Oncol. 2014;50(12):1165-1168.PubMedGoogle ScholarCrossref
50.
O’Brien  CJ, Traynor  SJ, McNeil  E, McMahon  JD, Chaplin  JM.  The use of clinical criteria alone in the management of the clinically negative neck among patients with squamous cell carcinoma of the oral cavity and oropharynx.  Arch Otolaryngol Head Neck Surg. 2000;126(3):360-365.PubMedGoogle ScholarCrossref
51.
Mishra  RC, Parida  G, Mishra  TK, Mohanty  S.  Tumour thickness and relationship to locoregional failure in cancer of the buccal mucosa.  Eur J Surg Oncol. 1999;25(2):186-189.PubMedGoogle ScholarCrossref
52.
Hanahan  D, Weinberg  RA.  Hallmarks of cancer: the next generation.  Cell. 2011;144(5):646-674.PubMedGoogle ScholarCrossref
53.
Xu  Y, Lefèvre  M, Périé  S,  et al.  Clinical significance of micrometastases detection in lymph nodes from head and neck squamous cell carcinoma.  Otolaryngol Head Neck Surg. 2008;139(3):436-441.PubMedGoogle ScholarCrossref
54.
Woolgar  JA, Vaughan  ED, Scott  J, Brown  JS.  Pathological findings in clinically false-negative and false-positive neck dissections for oral carcinoma.  Ann R Coll Surg Engl. 1994;76(4):237-244.PubMedGoogle Scholar
55.
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.  Otolaryng Head Neck. 2015;153(3):8.PubMedGoogle Scholar
56.
Lawrence  MS, Sougnez  C, Lichtenstein  L,  et al; Cancer Genome Atlas Network.  Comprehensive genomic characterization of head and neck squamous cell carcinomas.  Nature. 2015;517(7536):576-582.PubMedGoogle ScholarCrossref
57.
Roepman  P, Kemmeren  P, Wessels  LFA, Slootweg  PJ, Holstege  FCP.  Multiple robust signatures for detecting lymph node metastasis in head and neck cancer.  Cancer Res. 2006;66(4):2361-2366.PubMedGoogle ScholarCrossref
58.
Poh  CF, Durham  JS, Brasher  PM,  et al.  Canadian Optically-Guided Approach for Oral Lesions Surgical (COOLS) trial: study protocol for a randomized controlled trial.  BMC Cancer. 2011;11:462.PubMedGoogle ScholarCrossref
×