title: Glucose metabolism in NSCLC is histology-specific and diverges the prognostic potential of 18FDG-PET for adenocarcinoma and squamous cell carcinoma.
abstract: BACKGROUND
  Biological features of non-small-cell lung carcinomas (NSCLCs) are important determinants for prognosis. In this study, differences in glucose metabolism between adeno- and squamous cell NSCLCs were quantified using the hypoxia and glycolysis-related markers glucose transporter 1 (GLUT1), carbonic anhydrase IX (CAIX), monocarboxylate transporter 1 (MCT1) and 4 (MCT4) vasculature, and 18-fluoro-2-deoxyglucose (FDG)-uptake. Relevance of these markers for disease-free survival (DFS) was analyzed.
  
  
  METHODS
  Patients with curatively resected stage I to II and resectable stage IIIA, cN0-1 adeno- or squamous cell NSCLC, of whom fresh-frozen lung resection biopsies and pretreatment FDG-positron emission tomography (PET) scans were available, were included in this study (n = 108). FDG-uptake was quantified by calculating total lesion glycolysis (TLG). Metabolic marker expression was measured by immunofluorescent staining (protein) and quantitative polymerase chain reaction (messenger ribonucleic acid [mRNA]). Patients were retrospectively evaluated for DFS.
  
  
  RESULTS
  mRNA and protein expression of metabolic markers, with the exception of MCT4, and TLG were higher in squamous cell carcinomas than in adenocarcinomas, whereas adenocarcinomas were better vascularized. Adenocarcinomas had a worse DFS compared with squamous cell carcinomas (p = 0.016) based on the potential to metastasize. High TLG was associated with a worse DFS only in adenocarcinomas.
  
  
  CONCLUSIONS
  Our findings suggest that the adenocarcinomas exhibit glycolysis under normoxic conditions, whereas squamous cell carcinomas are exposed to diffusion-limited hypoxia resulting in a very high anaerobic glycolytic rate. Although squamous cell carcinomas have a higher FDG-uptake, in general regarded as a poor prognostic factor, adenocarcinomas have a higher metastatic potential and a worse DFS. These findings show that FDG-PET should be interpreted in relation to histology. This may improve the prognostic potential of FDG-PET and may aid in exploiting FDG-PET in treatment strategies allied to histology.
authors.affiliation: Departments of *Pulmonary Diseases, †Radiation Oncology, ‡Pathology, and §Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Olga C J
authors.initials: OC
authors.lastname: Schuurbiers
authors.forename: Tineke W H
authors.initials: TW
authors.lastname: Meijer
authors.forename: Johannes H A M
authors.initials: JH
authors.lastname: Kaanders
authors.forename: Monika G
authors.initials: MG
authors.lastname: Looijen-Salamon
authors.forename: Lioe-Fee
authors.initials: LF
authors.lastname: de Geus-Oei
authors.forename: Miep A
authors.initials: MA
authors.lastname: van der Drift
authors.forename: Erik H F M
authors.initials: EH
authors.lastname: van der Heijden
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Oyen
authors.forename: Eric P
authors.initials: EP
authors.lastname: Visser
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000951:Antigens, Neoplasm / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D015687:Cell Hypoxia / Q000502:physiology; D018572:Disease-Free Survival; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D027981:Symporters / Q000378:metabolism; D059016:Tumor Microenvironment; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000951:Antigens, Neoplasm; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D019788:Fluorodeoxyglucose F18; D005947:Glucose; D051272:Glucose Transporter Type 1; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D019275:Radiopharmaceuticals; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C406962:SLC16A4 protein, human; C495677:SLC2A1 protein, human; C089226:CA9 protein, human