title: A quantitative histomorphometric classifier (QuHbIC) identifies aggressive versus indolent p16-positive oropharyngeal squamous cell carcinoma.
abstract: Human papillomavirus-related (p16-positive) oropharyngeal squamous cell carcinoma patients develop recurrent disease, mostly distant metastasis, in approximately 10% of cases, and the remaining patients, despite cure, can have major morbidity from treatment. Identifying patients with aggressive versus indolent tumors is critical. Hematoxylin and eosin-stained slides of a microarray cohort of p16-positive oropharyngeal squamous cell carcinoma cases were digitally scanned. A novel cluster cell graph was constructed using the nuclei as vertices to characterize and measure spatial distribution and cell clustering. A series of topological features defined on each node of the subgraph were analyzed, and a random forest decision tree classifier was developed. The classifier (QuHbIC) was validated over 25 runs of 3-fold cross-validation using case subsets for independent training and testing. Nineteen (11.9%) of the 160 patients on the array developed recurrence. QuHbIC correctly predicted outcomes in 140 patients (87.5% accuracy). There were 23 positive patients, of whom 11 developed recurrence (47.8% positive predictive value), and 137 negative patients, of whom only 8 developed recurrence (94.2% negative predictive value). The best other predictive features were stage T4 (18 patients; 83.1% accuracy) and N3 nodal disease (10 patients; 88.6% accuracy). QuHbIC-positive patients had poorer overall, disease-free, and disease-specific survival (P<0.001 for each). In multivariate analysis, QuHbIC-positive patients still showed significantly poorer disease-free and disease-specific survival, independent of all other variables. In summary, using just tiny hematoxylin and eosin punches, a computer-aided histomorphometric classifier (QuHbIC) can strongly predict recurrence risk. With prospective validation, this testing may be useful to stratify patients into different treatment groups.
authors.affiliation: Departments of *Pathology and Immunology †Otolaryngology Head and Neck Surgery ∥Radiation Oncology, Washington University, St Louis, MO §Division of Biostatistics ‡Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH.
authors.forename: James S
authors.initials: JS
authors.lastname: Lewis
authors.forename: Sahirzeeshan
authors.initials: S
authors.lastname: Ali
authors.forename: Jingqin
authors.initials: J
authors.lastname: Luo
authors.forename: Wade L
authors.initials: WL
authors.lastname: Thorstad
authors.forename: Anant
authors.initials: A
authors.lastname: Madabhushi
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000175:diagnosis* / Q000401:mortality / Q000556:secondary / Q000628:therapy / Q000821:virology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis*; D003661:Decision Support Techniques; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D009959:Oropharyngeal Neoplasms / Q000737:chemistry / Q000175:diagnosis* / Q000401:mortality / Q000473:pathology / Q000628:therapy / Q000821:virology; D030361:Papillomavirus Infections / Q000150:complications / Q000175:diagnosis / Q000821:virology; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D012307:Risk Factors; D013194:Staining and Labeling; D013997:Time Factors; D046888:Tissue Array Analysis; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16