Staging Guidelines May be Missing Biomarkers that Affect Outcomes in OPSCC


Researchers suggested that the 2017 classifications do not currently allow for uniform stratification and proper outcome prognostication for surgically treated patients with p16-positive oropharyngeal squamous cell carcinoma.

Extracapsular/extranodal extension (ECE) and HPV16 DNA status should be included in the prognostic staging of patients with p16-positive oropharyngeal squamous cell carcinomas (OPSCCs) because several lines of evidence demonstrate their impact on survival, according to a study published in Cancer.

Researchers also noted that their research suggests the eighth edition of the tumor, lymph node, metastasis classifications (TNM 2017), created by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC), does not allow for a uniform stratification and proper outcome prognostication for surgically treated patients with p16-positive OPSCC. 

“As long as sufficient consideration of ECE and HPV16 status is missing, a revision of the UICC staging system for primarily surgically treated patients with p16-positive OPSCC and the inclusion of these biomarkers, which exert an essential effect on outcome, appears to be required to overcome the limitations of the TNM 2017,” the authors wrote. 

Using a cohort of 92 patients with p16-positive, lymph node-positive (stage III-IVB) OPSCC who underwent surgery and neck dissection, researchers found that 66 of 92 patients (71.4%) were p16-positive/HPV16 DNA-positive, 62 of 92 (67%) were ECE-positive, and 45 of 62 (72.6%) were ECE-positive, p16-positive, and HPV16 DNA-positive. The mean numbers of positive lymph nodes in ECE-positive patients (5.0; 95% CI, 3.8-6.4) and ECE-negative patients (2.4; 95% CI, 1.8-2.9) were different (= 0.0007).

ECE affected overall survival (OS) and tumor-specific survival in those who were p16-positive (= 0.007 and P = 0.047, respectively) and those who were p16-positive/HPV16 DNA-positive (P = 0.013 and = 0.026, respectively). Relative to the unequal distributions of ECE-positive/HPV16 DNA-negative tumors, the TNM 2017 failed to discriminate OS in patients with UICC stage I, II, and III disease (mean OS, 54.5, 73.4, and 45 months respectively; median OS, 64.7 months, not reached, and 41.1 months, respectively).

According to a univariate CoxR, the appearance of ECE predicted impaired OS in patients with p16-positive OPSCC (hazard ratio [HR], 3.40; 95% CI, 1.17-9.89; = 0.025) and even greater impaired OS in those with p16-positive/HPV16 DNA-positive OPSCC (HR, 8.64; 95% CI, 1.12-66.40; = 0.038). Multivariate CoxR confirmed ECE and HPV16 DNA detection as independent predictors. 

“Staging systems like the TNM classification in oncology should express the level an extension of disease and provide an easy-to-obtain and user-friendly estimate for prognosis, simplifying decision-making for the appropriate therapy modalities,” the authors wrote. 

In 2002, 4 criteria characterizing staging and distinguishing the different groups were defined by Groome et al. They included:

  • Hazard consistency: patients within a group (stage) must have similar survival rates 

  • Hazard discrimination: perceptible differences in survival rates exist between the groups

  • Outcome prediction: high prediction of similar cure rates within a group

  • Balanced distribution of patients among the groups

The authors indicated that, at least in the studied cohort, the TNM 2017 failed to appropriately address these criteria. Positive ECE status and negative HPV16 DNA status affect the survival of patients who have p16-positive OPSCC and both are independent predictors in p16-positive OPSCC; however, as of now, both are also currently omitted from staging within TNM 2017. 

“Therefore, the TNM 2017 does not allow a uniform stratification and proper outcome prognostication for surgically treated patients with p16-positive OPSCC,” the authors wrote. “Rather, outside of randomized clinical trials, the treatment of p16-positive OPSCC should adhere to the current (unmodified) NCCN guidelines.”


Freitag J, Wald T, Kuhnt T, et al. Extracapsular Extension of Neck Nodes and Absence of Human Papillomavirus 16-DNA Are Predictors of Impaired Survival in p16-Positive Oropharyngeal Squamous Cell Carcinoma. Cancer. doi: 10.1002/cncr.32667.

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