# FAP-Directed Imaging and Therapy in Head and Neck Cancer of Unknown Primary

## TL;DR

This review explores how FAPI-PET/CT improves diagnosis and treatment of head and neck cancer of unknown primary by targeting the tumor microenvironment.

## Contribution

The paper highlights FAPI-PET/CT as a novel and superior imaging and therapeutic approach for HNCUP.

## Key findings

- FAPI-PET/CT outperforms FDG-PET/CT in detecting tumors in HNCUP cases.
- FAPI-PET/CT can guide FAP-directed radioligand therapies for patients with widespread disease.
- The review emphasizes FAPI-PET/CT's potential to improve diagnostic accuracy and therapeutic decisions in HNCUP.

## Abstract

Head and neck cancer of unknown primary (HNCUP) poses significant diagnostic challenges, as [18F]FDG positron emission tomography/computed tomography (PET/CT) often fails to detect tumor. Fibroblast activation protein inhibitor (FAPI) PET/CT has emerged as a promising alternative by targeting the tumor microenvironment and has shown improved diagnostic potential. This review summarizes the current evidence on FAPI-PET in HNCUP.

Cancer of unknown primary in the head and neck (HNCUP) region poses a major diagnostic and therapeutic challenge. While [18F]FDG positron emission tomography/computed tomography (PET/CT) is widely used for oncologic staging, it frequently fails to accurately identify the primary tumor in HNCUP cases, limiting its diagnostic accuracy and clinical utility. In contrast, Gallium-68 or F-18-labelled fibroblast activation protein inhibitor (FAPI) PET/CT has emerged as a promising alternative by selectively targeting cancer-associated fibroblasts, which are abundant in the tumor microenvironment. In recent years, FAPI-PET/CT has been increasingly investigated as a complementary or superior imaging modality to FDG-PET/CT for tumor detection in HNCUP, with potential implications for patient management. In a theranostic setting, patients with widespread disease demonstrating increased target expression on FAPI-PET have also been treated using Lutetium-177-labeled FAP-directed therapeutic equivalents. This review provides a comprehensive overview of the current evidence on FAPI-PET/CT in HNCUP, emphasizing its diagnostic advantages, potential impact on therapeutic decision making, and future directions for research in this evolving field, including FAP-directed radioligand therapies.