Background: Head and neck squamous cell carcinoma (HNSCC) remains the seventh most common cancer worldwide, characterized by late-stage diagnosis and poor 5-year survival rates. Oral squamous cell carcinoma (OSCC) is the most prevalent subtype. The identification of robust diagnostic, prognostic, and predictive markers is essential for personalized treatment monitoring. Methods: Following PRISMA and PICO standards, we conducted a comprehensive review of studies published over the past 10 years across PubMed/MEDLINE, Scopus, and Web of Science. The selection process was facilitated by AI-powered tools (Rayyan QCRI), and study quality was assessed using NOS or QUIPS. Results: 34 articles (including meta-analyses and original trials) were identified. Established clinical markers, such as p16-positivity (HR ≈ 0.55) and PD-L1 (CPS), remain significant. However, the molecular landscape is expanding to include high-risk lncRNA signatures (HR ≈ 2.50), immune checkpoints such as TIGIT (HR ≈ 1.85), and genomic alterations, including IL-10 promoter polymorphisms. We highlight that epigenetic silencing of p16 affects only about 25% of patients, while metabolic regulators (e.g., GLUT-1) and protein markers (e.g., MASPIN) offer critical predictive value for therapy response. Conclusions: The diagnostic and predictive paradigm is shifting toward a multi-omic approach that integrates DNA, RNA, proteins, and metabolic indicators. Future clinical use will rely on AI-driven multimarker panels and non-invasive liquid biopsies to enable real-time monitoring and de-escalation of treatment strategies.

Background/Objectives: Oral mucosal melanoma is rare and associated with poor prognosis. This study aims to identify clinical and molecular factors influencing survival by synthesizing published cases together with one original case. Methods: A systematic review was conducted. Relevant clinical, histopathological, and follow-up parameters were compared across studies. Results: A total of 21 publications describing 42 patients were reviewed, and the data were aggregated with our patient, yielding 43 patients in total. Our case describing a 66-year-old male with 14 years of disease-free survival despite multiple excisions illustrated the potential for long-term survival despite poor prognosis. Favorable prognostic indicators listed in the literature included preserved expression of BAP1, p53, BCL2, and p16, the presence of tumor-infiltrating lymphocytes, smaller tumor size and thickness, and the absence of vascular invasion. Longer follow-up periods were most often observed in younger patients without lymphadenopathy, distant metastasis, or local recurrence. Conclusions: This review highlights prognostic features in oral mucosal melanoma but also underscores exceptions, demonstrating that survival cannot be fully explained by current clinical and molecular criteria.