In the early 21 st century, integrating positron emission tomography (PET) with CT enabled the detection of abnormal metabolic activity--a hallmark of cancer cells--facilitating the more accurate localization of primary tumors [3]. Concurrently, advancements in molecular biology provided more profound insights into tumors' genetic and molecular profiles, opening new avenues for diagnosis, prognosis, and treatment [1]. Today, the diagnostic approach is increasingly multidisciplinary, involving oncologists, radiologists, surgeons, and molecular biologists to ensure personalized and effective therapeutic strategies. These developments have enhanced diagnostic accuracy and improved outcomes for patients with challenging malignancies. The etiology of CUPs in the head and neck region is multifactorial, with environmental and biological factors contributing to tumor development. Habits of tobacco and alcohol use act by significantly increasing the likelihood of developing malignancies in this anatomical region and are, thus, among the primary risk factors. Occupational exposure to carcinogens, such as wood dust and industrial chemicals, has also been implicated in specific subsites, including the nasal cavity and paranasal sinuses. Poor oral hygiene and chronic irritation have also been identified as potential contributors to carcinogenesis in the oral cavity [1; 2]. A growing body of evidence highlights the critical role of viral oncogenesis, particularly the involvement of human papillomavirus (HPV) and Epstein-Barr virus (EBV). HPV, particularly its high-risk strains, such as HPV-16 and HPV-18, has been strongly associated with oropharyngeal squamous cell carcinomas, where it is considered a major etiological factor. These tumors are biologically distinct, often presenting in younger, nonsmoking patients, and have been linked to better prognoses compared to HPV-negative counterparts. Similarly, EBV has been predominantly associated with nasopharyngeal carcinoma, contributing to its pathogenesis through latent infection and the expression of oncogenic viral proteins. The interplay between these risk factors underscores the complexity of CUPs and highlights the importance of a comprehensive diagnostic pathway that includes viral testing. Identifying HPV and EBV status not only aids in localizing the primary tumor site, but also provides valuable prognostic information and guides treatment strategies, reflecting the growing emphasis on precision medicine in oncology. The first clinical presentation of a patient with squamous cell carcinoma of the head and neck district (HNSCC) can notoriously be nonspecific, and so is the finding, at first glance, of a cervical swelling as per metastatic lymphadenopathy, which may constitute the unique expression of a squamous cell carcinoma arising from an adjacent region. Such a malignancy is defined as cancer of unknown primary site (CUP), accounting for less than 5% of tumors within the anatomical district [1]. Standard algorithms for the detection of the primary tumor involve multidisciplinary teams (ENT, OMFS, radiologists, radiotherapists, medical oncologists) and include comprehensive physical examination, in-office panendoscopy with directed biopsies of mucosal subsites (those with a pathognomic aspect or likely to harbor the hidden primary), diagnostic imaging studies with computed tomography (CT), magnetic resonance imaging (MRI), and 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) [2]. Computed tomography (CT) has a diagnostic accuracy in detecting residual or recurrent disease that can be estimated at 67.9% [3], considering a spatial resolution of 0.23-0.625 mm, improved contrast resolution using novel and advanced algorithms, and crosswise specificity and sensitivity that change according to anatomic district and pathology [4; 5].