This review is a call for mindfulness and precision when applying TNM 8 in oropharyngeal cancers. Implications, intentions, and weaknesses of TNM 8 are addressed in light of our own investigations and the published literature. In TNM 8, the impact of p16INK4A status on the staging of oropharyngeal SCC highlights i) that underlying evidence is scarce, ii) its stage grouping exclusively has prognostic intention, and iii) that a noncritical application of TNM 8 might negatively impact the patients' survival as the perception of TNM 8 as having therapeutic intention may lead to de-escalating treatment regimens in p16INK4A-positive cases, specifically when grouped into stage I despite the presence of neck metastasis. If other parameters from HPV positivity that also have a negative impact on the patient's survival, such as smoking or the presence of comorbidity, are neglected in therapy planning, survival outcomes might even become worse. Future studies applying TNM 8 and further investigating the value of p16INK4A as surrogate marker for active HPV infections will identify whether or not changes in TNM 8 should have therapeutic implications in HPV-associated, only p16INK4A-positive cases or whether this impact additionally holds true for nontonsillar cancers.

(1) Background: Evaluation of impact of adjuvant radiation therapy (RT) in patients with oral squamous cell carcinoma of the oral cavity/oropharynx (OSCC) of up to 4 cm (pT1/pT2) and solitary ipsilateral lymph node metastasis (pN1). A non-irradiated group with clinical follow-up was chosen for control, and survival and quality of life (QL) were compared; (2) Methods: This prospective multicentric comprehensive cohort study included patients with resected OSCC (pT1/pT2, pN1, and cM0) who were allocated into adjuvant radiation therapy (RT) or observation. The primary endpoint was overall survival. Secondary endpoints were progression-free survival and QL after surgery; (3) Results: Out of 27 centers, 209 patients were enrolled with a median follow-up of 3.4 years. An amount of 137 patients were in the observation arm, and 72 received adjuvant irradiation. Overall survival did not differ between groups (hazard ratio (HR) 0.98 [0.55–1.73], p = 0.94). There were fewer neck metastases (HR 0.34 [0.15–0.77]; p = 0.01), as well as fewer local recurrences (HR 0.41 [0.19–0.89]; p = 0.02) under adjuvant RT. For QL, irradiated patients showed higher values for the symptom scale pain after 0.5, two, and three years (all p < 0.05). After six months and three years, irradiated patients reported higher symptom burdens (impaired swallowing, speech, as well as teeth-related problems (all p < 0.05)). Patients in the RT group had significantly more problems with mouth opening after six months, one, and two years (p < 0.05); (4) Conclusions: Adjuvant RT in patients with early SCC of the oral cavity and oropharynx does not seem to influence overall survival, but it positively affects progression-free survival. However, irradiated patients report a significantly decreased QL up to three years after therapy compared to the observation group.