## 4 Discussion  
The anatomical subsites responsible for the onset of the primary tumor within the head and neck region are crucial because they guide very different diagnostic and therapeutic choices and indications. Lateral-cervical neoplastic lymph-adenopathies are expressions of different primary tumors depending on their level of localization, thus delineating a pattern of lymph node metastasis, which is cardinal to reach the most likely anatomical subsite of tumor occurrence. In our experience, the great majority of patients discussed in Head and Neck Tumor Board ranging from the year 2016 and 2023 had laryngeal tumors, followed by oral cavity primaries, then oropharyngeal, nasopharyngeal, and hypopharyngeal tumors; the rarest finding was of nasal, paranasal sinuses, ear, and skin tumors. Of the population in our case series, about 5% presented with a CUP. In the 2019 group of patients, a total percentage of 64% of studied individuals presenting with an unspecific cervical mass ended up with a cancer of unknown origin, either because of their death before the identification of the primary tumor or of the impossibility itself to identify the primary site of onset of their neoplasm. The great majority of diagnosed patients presented an oropharyngeal, nasopharyngeal, or oral cavity primary tumor. Our findings emphasize that the oropharynx is notoriously the most frequent site of origin of occult cancers in the head and neck region [11]. Other sites of origin of HNCUPs are the other pharyngeal districts and the oral cavity; where district lymph nodes of the neck are involved, the level of node metastasis suggests the location of the primary carcinoma; in this sense, levels I-III cervical node metastasis often correlate with oral cavity carcinomas; levels II-IV often correlate with oropharynx, hypopharynx, and larynx primaries; and level V usually correlates with nasopharyngealnx and cutaneous carcinomas [12]. A failure in the early identification of primary carcinoma results in the patient being treated with large radiotherapy fields, despite the evidence that such aggressive treatment leads to several adverse effects and poor outcomes. Similarly, further therapeutic approaches other than radiotherapy, when administered to a patient with an HNCUP, are more nonspecific and burdened with more adverse effects than benefits in terms of the  
Figure 1: Diagnosis of tumor (%) in the 28 patients selected. outcome. However, the most current evidence suggests that patients with an HNCUP who undergo surgery or radio-chemotherapy experience greater survival rates than the overall group of untreated patients, regardless of whether the location of the primary tumor is known. Therefore, early identification of the primary tumor is crucial in terms of patient prognosis, since it allows a prompt initiation of the therapeutic pathway, the planning of which is impossible if the site of primary tumor onset remains unknown. Patients diagnosed with a CUP have generally a worse prognosis than those with metastatic cancer of known origin, suggesting that tissue of origin identification and site-specific therapy enhance a patient's survival and prognosis [13]. Therefore, spatial diagnosis is focal, along with histo-cytopathological characterization. Spatial diagnosis is given by imaging, since macroscopically visible lesions on endoscopy are rare, especially in the earliest stages. Consequently, the histological characterization of the lesion becomes arduous and not always feasible. The histologic identification of HPV and EBV is undoubtedly supportive in circumstantiating the anatomic subsite of primary localization, in parallel with an in-depth clinical history, focusing on exposure to risk factors primarily involved in carcinogenesis within the head and neck region [14]. The detection of HPV status is implied in the HNCUP diagnostic process (especially in oropharyngeal primary carcinomas) and is achieved with immunohistochemistry (IHC) detection of p16, in situ hybridization (ISH), or polymerase chain reaction (PCR) of HPV DNA.