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Original Investigation |

The Origin of Regional Failure in Oral Cavity Squamous Cell Carcinoma With Pathologically Negative Neck Metastases

Moran Amit, MD, MSc1,2; Tzu Chen Yen, MD, PhD3; Chun Ta Liao, MD3; Pankaj Chaturvedi, MD4; Jai Prakash Agarwal, MD4; Luiz Paulo Kowalski, MD, PhD5; Hugo F. Kohler, MD5; Ardalan Ebrahimi, MBBS6,7; Jonathan R. Clark, MBBS6; Claudio Roberto Cernea, MD, PhD8; Jose S. Brandao, MD8; Matthias Kreppel, MD, PhD9; Joachim E. Zöller, MD9; Leonor Leider-Trejo, MD10; Gideon Bachar, MD11; Thomas Shpitzer, MD11; Andrea Villaret Bolzoni, MD12; Raj P. Patel, MD13; Sashikanth Jonnalagadda, MD14; Thomas Kevin Robbins, MD15; Jatin P. Shah, MD14; Snehal G. Patel, MD15; Ziv Gil, MD, PhD1,2
[+] Author Affiliations
1Laboratory for Applied Cancer Research, Clinical Research Institute at Rambam, Haifa, Israel
2Department of Otolaryngology–Head and Neck Surgery, Rambam Medical Center, Rappaport School of Medicine, the Technion, Israel Institute of Technology, Haifa, Israel
3Chang Gung Memorial Hospital, Taoyuan, Taiwan
4Tata Memorial Hospital, Mumbai, India
5A.C. Camargo Cancer Center, São Paulo, Brazil
6Sydney Head and Neck Cancer Institute, Royal Prince Alfred Hospital, Sydney, Australia
7Australian School of Advanced Medicine, Macquarie University, Sydney, Australia
8Department of Head and Neck Surgery, University of São Paulo Medical School, São Paulo, Brazil
9Department of Oral and Cranio-Maxillo and Facial Plastic Surgery, University of Cologne, Germany
10Department of Pathology, Tel Aviv Medical Center, Tel Aviv, Israel
11Department of Otolaryngology–Head and Neck Surgery, Rabin Medical Center, Petach Tikva, Israel
12Department of Otorhinolaryngology, University of Brescia, Brescia, Italy
13University of Auckland, Auckland, New Zeeland
14Southern Illinois University School of Medicine, Springfield
15Head and Neck Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
JAMA Otolaryngol Head Neck Surg. 2014;140(12):1130-1137. doi:10.1001/jamaoto.2014.1539.
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Importance  Squamous cell carcinoma of the oral cavity (OSCC) is a common malignant tumor worldwide.

Objective  To determine if regional failure in patients with OSCC and pathologically negative neck nodes (pN–) is due to an incomplete sampling procedure during surgery.

Design, Setting, and Participants  We retrospectively reviewed the medical records of 2258 patients from 11 cancer centers worldwide who underwent neck dissection for OSCC (1990-2011) and who were pN−. Of those, 345 had clinical evidence of nodal metastases (cN+) on radiologic workup. The neck specimens were available for reanalysis in 193 patients. Survival rates were calculated using the Kaplan-Meier graphs and analyzed by multivariable analysis.

Main Outcomes and Measures  Five-year overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS).

Results  Resectioning and analysis of the neck dissection specimens in the cN+/pN− subgroup revealed false-negative results in 29 (15%) of 193 patients. The negative predictive value of the initial pathologic examination was 85%. The 5-year OS and DSS in the cN−/pN− group were 77.6% and 87.2%, respectively. The 5-year OS and DSS of the cN+/pN− group were 62.6% and 78.5%, respectively (P < .001). In multivariable analysis, cN+ classification was significantly associated with poor OS (hazard ratio [HR], 1.7; 95% CI, 1.1-3.8; P = .03) and poor DSS (HR, 1.46; 95% CI, 1.1-4.1; P = .04). A cN+ classification was associated with lower DFS (66.3% vs 76.2%; P = .05) and lower regional recurrence–free survival (68.6% vs 78.8%; P = .02) but not with local (P = .20) or distant recurrence (P = .80).

Conclusions and Relevance  Pathologic staging underestimates the incidence of nodal metastases in cN+ disease. After correction for pathologically missed nodal metastases, radiologic evidence of neck nodes is an independent predictor of outcome, suggesting that traditional sampling during surgery might miss metastases, and this fact might explain the origin of treatment failure in these patients.

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Figures

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Figure 1.
Pathologic Images From a Representative Case of Revised Pathology

A, Pathologic sample originally read as negative for metastasis. B, Pathologic sample after resectioning prompted a change in reading to positive for metastasis. Original magnification ×20 and hematoxylin-eosin stain for both panels.

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Figure 2.
Kaplan-Meier Survival Graphs in Patients With Pathologically Negative Neck Nodes by Clinical Nodal Status

A, Five-year overall survival. B, Five-year disease-specific survival. Both graphs are calculated using Kaplan-Meier analysis of patients with pathologically negative neck nodes after revision of the pathology. cN+ indicates patient with clinically positive neck nodes (n = 164); cN−, clinically negative neck nodes (n = 1913).

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Figure 3.
Kaplan-Meier Patterns of Survival and Failure Rates in Patients With Pathologically Negative Neck Nodes by Clinical Nodal Status

A, Five-year disease-free survival. B, Five-year local recurrence-free survival. C, Five-year regional recurrence-free survival. D, Distant metastasis failure rate calculated using the Kaplan-Meier analysis. cN+ indicates patient with clinically positive neck nodes (n = 164); cN−, clinically negative neck nodes (n = 1913).

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