Validation of Methods for Oropharyngeal Cancer HPV Status Determination in US Cooperative Group Trials

被引:303
作者
Jordan, Richard C. [1 ,2 ,3 ]
Lingen, Mark W. [4 ]
Perez-Ordonez, Bayardo [8 ]
He, Xin [5 ]
Pickard, Robert [6 ]
Koluder, Michael [6 ]
Jiang, Bo [6 ]
Wakely, Paul [7 ]
Xiao, Weihong [6 ]
Gillison, Maura L. [6 ]
机构
[1] Univ Calif San Francisco, Dept Orofacial Sci, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA
[3] Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94140 USA
[4] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA
[5] Univ Maryland, Dept Biostat, College Pk, MD 20742 USA
[6] Ohio State Univ, Viral Oncol Program, Ctr Comprehens Canc, Columbus, OH 43210 USA
[7] Ohio State Univ, Med Ctr, Dept Pathol, Columbus, OH 43210 USA
[8] Univ Toronto, Dept Pathol, Univ Hlth Network, Toronto, ON, Canada
关键词
HPV; oropharyngeal carcinoma; scoring; p16; SQUAMOUS-CELL CARCINOMA; IN-SITU HYBRIDIZATION; PHASE-III TRIAL; HUMAN-PAPILLOMAVIRUS; NECK-CANCER; PROGNOSTIC-SIGNIFICANCE; FAVORABLE PROGNOSIS; TUMOR-ORIGIN; HEAD; SURVIVAL;
D O I
10.1097/PAS.0b013e318253a2d1
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Tumor human papillomavirus (HPV) status is a prognostic factor for oropharyngeal cancer, but classification methods are not standardized. Here we validate the HPV classification methods used in US cooperative group trials. Tumor DNA and RNA purified from 240 paraffin-embedded oropharyngeal cancers diagnosed from 2000 to 2009 were scored as evaluable if positive for DNA and mRNA controls by quantitative polymerase chain reaction (PCR). Eighteen high-risk (HR) HPV types were detected in tumors by consensus PCR, followed by HR-HPV E6/7 oncogene expression analysis by quantitative reverse transcriptase PCR. The sensitivity (S), specificity (SP), and positive (PPV) and negative predictive values (NPV) of p16 expression detected by immunohistochemistry (IHC) and HPV16 detected by in situ hybridization (ISH) were evaluated in comparison with HR-HPV E6/7 oncogene expression. Interrater agreement among 3 pathologists was evaluated by kappa statistics. Of 235 evaluable tumors, 158 (67%; 95% confidence interval, 61.2-73.3) were positive for HR-HPV E6/7 oncogene expression [HPV type 16 (92%), 18 (3%), 33 (3%), 35 (1%), or 58 (1%)]. p16 IHC had high sensitivity (S 96.8%, SP 83.8%, PPV 92.7%, and NPV 92.5%), whereas HPV16 ISH had high specificity (S 88.0%, SP 94.7%, PPV 97.2%, and NPV 78.9%) for HR-HPV oncogene expression. Interrater agreement was excellent for p16 (kappa = 0.95 to 0.98) and HPV16 ISH (kappa = 0.83 to 0.91). Receiver operating curve analysis determined the cross-product of p16 intensity score and percentage of tumor staining to optimally discriminate HR-HPV E6/7-positive and HR-HPV E6/7-negative tumors. p16 IHC and HPV16 ISH assays show excellent performance, with high sensitivity and specificity, respectively. A new validated H-score for p16 IHC assessment is proposed. Appropriate assay choice depends on clinical implications of a false-positive or false-negative test.
引用
收藏
页码:945 / 954
页数:10
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