## 2 Materials and Methods  
We retrospectively selected case series ranging from the years 2016 and 2023, and a total amount of 5323 patients was identified for the present study, as shown in Table 1, by those in charge of the Department of Radiology, Oncology and Pathologic Anatomy--Diagnostic Medicine and Radiology--of Policlinico Umberto I Sapienza University of Rome. The diagnostic-therapeutic pathway for all of them was included in the collegial Head and Neck Unit Tumor Board, a multidisciplinary collaboration of specialists in Otolaryngology, Oral and Maxillofacial Surgery, Oncology, Radiotherapy, Pathologic Anatomy, Radiology, Neuroradiology, and Nuclear Medicine. The current analysis focused on patients taken in charge and discussed in the multidisciplinary tumor board in 2019, which comprised 605 patients; of these patients, all individuals primarily presenting with lateral-cervical mass were considered and included in the present study, focusing on only those with uncertainty in the diagnosis of the primary tumor, thus eliminating from the study all patients whose characteristics are listed in Table 2 (exclusion criteria). A total amount of 28 patients met the criteria. All the selected patients were studied using the best-practice imaging available modalities, either singularly or using more than one modality concurrently, as defined and codified in the most up-to-date guidelines for diagnosis. Each patient underwent a multimodal diagnostic pathway, including ultrasound, CT, MRI, and PET-CT, performed according to the following radiological parameters. Ultrasound (Samsung): High-resolution ultrasound (probe frequencies \(\geq\)7.5 MHz) was used to evaluate cervical lymph nodes. The examination was completed with elastography using a standard elasticity scale. The US also guided lymph node biopsies using 22-25 G needles (FNAB). CT (Philips): CT was performed with thin-slice volumetric acquisitions (0.5-0.75 mm) and intravenous contrast agents (1.5 mL/kg, injection rate 2.5-3 mL/s) to enhance visualization of vascular and nodal structures. Multiplanar image reconstruction used advanced algorithms to optimize spatial and contrast resolution. MRI (GE 3 T): MRI was acquired with high spatial resolution sequences (\(1.0\times 1.0\times 2.0\) mm\({}^{3}\)) in T1, T2, dedicated neck coil, and diffusion-weighted imaging (DWI), including fat-suppressed and gadolinium-enhanced (0.1 mmol/kg) sequences. Special attention was given to evaluating perineural invasion and differentiating recurrence from post-treatment fibrosis. PET-CT: PET-CT (GE Medical System Healthcare) with 18F-FDG was performed using a standard protocol (dose 3.7 MBq/kg), with scans started 60 min after tracer injection. CT images using 1 mm slices, while PET image processing used iterative algorithms (e.g., Q.Clear) to improve signal-to-noise ratio and diagnostic accuracy to resolution of 1 mm. The data obtained from patients diagnosed with CUP were then reassessed after 5 years from the first encounter to evaluate the prosecution of the diagnostic-therapeutic course. \begin{table}
\begin{tabular}{c c} \hline
**Nr.** & **Exclusion Criteria** \\ \hline
1 & Patients with specific diagnosis of primary HNSCC on lymph node fine-needle aspiration biopsy (FNAB) \\
2 & Patients with certain diagnosis of primary tumor other than HNSCC (melanoma, sarcoma, etc.) on lymph-node fine-needle aspiration biopsy (FNAB) \\
3 & Patients with hematological/hemopoietic malignancy, lymphatic, and lymphocytetopic tumors. \\
4 & Patients aged \(<\)18 years old \\
5 & Patients with thyroid goiter or nodular thyroidopathy. \\ \hline \end{tabular}
\end{table} 
Table 2: Exclusion criteria for patients identified in the study. \begin{table}
\begin{tabular}{c c} \hline
**Year** & **NR. of Discussed Cases** \\ \hline
2016 & 516 \\
2017 & 642 \\
2018 & 722 \\
2019 & 605 \\
2020 & 638 \\
2021 & 620 \\
2022 & 782 \\
2023 & 798 \\ Total & 5323 \\ \hline \end{tabular}
\end{table} 
Table 1: Patients discussed in the Multidisciplinary Head and Neck Tumor Board from 2016 to 2023.