# Detecting Occult Sentinel Node Metastases in HNSCC: The Emerging Role of lncRNAs as Biomarkers and Future Perspectives for USgFNAB Molecular Profiling

## TL;DR

This review explores how long non-coding RNAs (lncRNAs) could improve the detection of hidden lymph node metastases in head and neck cancer using ultrasound-guided biopsies.

## Contribution

The paper highlights the potential of lncRNAs as biomarkers for improving the sensitivity of USgFNAB in detecting early metastases in HNSCC.

## Key findings

- Several lncRNAs, such as HOTAIR and MALAT1, are associated with metastatic progression in HNSCC.
- Elevated lncRNA expression correlates with advanced tumor stage and poor patient survival.
- Current studies lack lncRNA profiling in matched primary tumors and metastatic lymph nodes.

## Abstract

The spread of head and neck cancer to lymph nodes in the neck strongly affects treatment decisions and patient outcomes, yet current diagnostic methods often fail to detect small or early metastases before treatment begins. Ultrasound-guided fine-needle aspiration biopsy is a widely used, minimally invasive test, but its ability to detect hidden metastases is limited. Recent research shows that long non-coding RNAs, a class of stable genetic molecules involved in cancer progression, may serve as sensitive molecular markers of metastatic disease. This review summarizes the current evidence on the role of these molecules in head and neck cancer and discusses how their analysis in biopsy samples could improve the detection of occult lymph node metastases. Integrating molecular biomarkers with existing diagnostic protocols has the potential to reduce unnecessary surgery, improve treatment planning, and ultimately enhance patient outcomes.

Background: Accurate detection of cervical lymph node metastases is a critical determinant of prognosis and treatment planning in head and neck squamous cell carcinoma (HNSCC). Although ultrasound-guided fine-needle aspiration biopsy (USgFNAB) is widely used as a minimally invasive diagnostic tool, its sensitivity for detecting occult metastases remains limited. Current preoperative staging modalities are further constrained by operator dependency and suboptimal specificity in early-stage disease. Integration of molecular diagnostics, particularly the analysis of long non-coding RNAs (lncRNAs), represents a promising strategy to enhance diagnostic accuracy. Objective: This review synthesizes the current evidence on lncRNA expression profiles in HNSCC, with an emphasis on their association with lymph node metastasis and potential application in FNAB-derived material for pre-treatment staging. Methods: A structured literature search was conducted, focusing on studies evaluating lncRNA expression profiles in HNSCC and their relevance to lymph node metastasis, with a particular focus on the feasibility of analysis of USgFNAB samples. Results: Multiple lncRNAs, including HOTAIR, MALAT1, UCA1, TUG1, AFAP1-AS1, H19, MEG3, and ADAMTS9-AS2, have been implicated in metastatic progression through their involvement in diverse mechanisms such as epithelial-to-mesenchymal transition, chromatin remodeling, angiogenesis, and pre-metastatic niche formation. Elevated expression of several of these transcripts correlates with adverse clinicopathological features, including advanced tumor stage, extranodal extension, and reduced survival. However, no studies have profiled lncRNA expression in matched primary tumors and metastatic lymph nodes, and transcriptomic analysis of FNAB samples remains largely unexplored in HNSCC. Conclusions: lncRNAs represent promising molecular biomarkers for enhancing the sensitivity and specificity of USgFNAB in detecting occult cervical metastases. Future research should prioritize paired tumor–node lncRNA profiling, validation of FNAB-based molecular assays, and integration of multi-omics data for predictive modeling. Overall, integrating lncRNA analysis into ultrasound-guided fine-needle aspiration biopsy may enhance the detection of occult nodal metastases in head and neck squamous cell carcinoma and support more accurate nodal staging in clinically node-negative patients.