Electronic nose versus gas chromatography – mass spectrometry for diagnostic discrimination of advanced hepatocellular carcinoma by volatolomic analysis

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC), the third leading cause of cancer-related mortality, is often diagnosed late due to lack of early symptoms. Electronic nose (eNose) technology has been used to detect volatile organic compounds (VOCs) in exhaled breath with moderate accuracy. This study investigated eNose versus gas chromatography-mass spectrometry (GC-MS) for volatolomic analysis of blood and urine headspace to improve HCC diagnosis. METHODS: A prospective study enrolled 110 volunteers at Alexandria University Hospital, with 98 included (48 HCC patients, 50 matched controls) under strict criteria and ethical approval. Blood and urine samples were collected, clinically characterised, and analysed for alpha-fetoprotein (AFP) and haematological parameters, then blindly tested using a portable eNose with ten metal oxide sensors. Complementary GC-MS analysis with rigorous calibration enabled robust identification and quantification of halogenated and aromatic VOCs. RESULTS: HCC patients and controls were similar in age and sex, but HCC patients had lower body weight, haemoglobin, and platelet counts, with markedly elevated AFP and most classified at advanced Barcelona Clinic Liver Cancer (BCLC) stage IIIB. eNose analysis revealed distinct VOC signatures, with PCA outperforming LDA (> 85% accuracy in blood, ~ 100% in urine). GC-MS analysis confirmed disease-specific metabolic fingerprints, characterized by increased accumulation of halogenated compounds and reduced levels of aromatic hydrocarbons, including 1,1-dichloroethane. CONCLUSIONS: VOC profiling using eNose and GC-MS reliably distinguished advanced stage HCC patients from healthy controls, underscoring its promise as a fast, non-invasive diagnostic tool for improved HCC clinical management.