## 4 Discussion
Likewise, ISH detection of the Epstein-Barr encoding region (EBER) is performed in a nasopharyngeal carcinoma (NPC), and in such cases has largely proved to be relevant. There are currently very few other useful tumor markers and IHC analyses regarding cancers of the head and neck region. Actually, those available biomarkers roughly allow the differentiation of the broad cancer types, such as carcinomas, melanomas, lymphomas, and sarcomas [15]. At present, other molecular markers that can more specifically indicate the histological subtypes of tumor masses are being studied. These markers will contribute to an increasingly precise and in-depth definition of the primary tumor, enabling a more effective treatment based on the existence of positive and negative prognostic factors linked precisely to the specific detected tumor. In addition, certain molecular biomarkers highlighted in secondary masses or metastases could help characterize the primary tumor, perhaps helping to precisely locate its topographical site of origin within head and neck locations. Regarding imaging techniques commonly used in the diagnostic pathway of patients presenting with tumors that turn out to be a CUP, some considerations are mandatory. The spatial resolution of CT can vary depending on the protocol used. Current evidence indicates that the spatial resolution of standard CT can reach values of 0.23 mm and 0.625 mm in coronary scans [4]. Contrast resolution, on the other hand, depends on the ability of CT to distinguish between tissues with minimal density differences. Precision in the density measurement--i.e., accuracy--of small volumes can be affected by the spatial resolution and the resolution model used [16]. The spatial resolution in MRI can be extremely high, as can its contrast resolution. For example, advanced techniques, such as ICE-DICE MRI, allow a spatial resolution of 1.0 \(\times\) 1.0 \(\times\) 2.0 mm\({}^{3}\); the high and extremely variable contrast resolution--depending on sequences--is particularly useful in distinguishing between different types of soft tissues; the high accuracy of MRI for evaluating extra-capsular extensions in the study of lymphadenopathy is notably helpful in CUPs [6]. The spatial resolution of images in a PET-CT equipped with 18F-FDG can be improved from 6 mm to 3 mm in axial scans; the contrast resolution exploits a method that improves the image contrast by significantly increasing the uptake ratio between lesions and the background, compared with the standard bicubic interpolation method. Regarding lymph nodes, current evidence asserts that the average SUVmax value is between 6.31 \(\pm\) 2.74 and 7.17 \(\pm\) 2.91 in metastatic neck lymph nodes [17]. An SUVmax \(\geq\) 3.16 was associated with a sensitivity of 74.4% and specificity of 84.9% for detecting lymph node metastasis in the neck [18]. The primary lymph node/tumor SUV ratio (SUVLN/SUVT) seems to improve the accuracy in assessing lymph node metastasis. The optimal cut-off value for the SUVLN/SUVT is 0.28, with a sensitivity of 90% and a specificity of 68% for predicting nodal malignancy [19]. This ratio is also used for the diagnosis of cervical lymph node metastasis in patients with laryngeal cancer. A cut-off of 1.08 for the SUVLN/SUVL showed a sensitivity of 84.1% and a specificity of 76% [20]. In patients with an HNCUP who undergo radiological examinations, at first glance, it is usually recommended to expand TC imaging from the skull base and neck to the thorax, as metastatic later-cervical lymphadenopathy or a primary carcinoma can easily involve the mediastum; for this reason, the scans must go down to the carina. In patients with multi-station and/or lower nodal involvement, FDG-PET might be the best choice because of its significant sensitivity in detecting distant and nodal metastases. Combining imaging methodologies--tomography and MRI--helps increase the sensitivity.