OBJECTIVES The aim of our study was to analyze the specificity and sensitivity of integrated positron emission tomography and computed tomography (PET/CT) in detecting nodal metastasis according to histology (adenocarcinoma vs squamous cell carcinoma), and to identify the factors related to false-negative findings. METHODS A retrospective, single-institution review of 353 consecutive patients with suspected or pathologically proven, potentially resectable non-small-cell lung cancer (NSCLC) who had integrated PET/CT scanning at the same centre. Lymph node staging was pathologically confirmed on tissue specimens obtained at mediastinoscopy and/or thoracotomy. Statistical evaluation of PET/CT results was performed on a per-patient and per-nodal-station basis. RESULTS A total of 2286 nodal... stations (1643 mediastinal, 333 hilar and 310 intrapulmonary) were evaluated. Adenocarcinoma was the final diagnosis in 244 patients and squamous carcinoma in 109 patients. Nodes were positive for malignancy in 80 (32.8%) of 244 patients with adenocarcinoma (N1 = 31; N2 = 48 and N3 = 1) and in 32 (29.3%) of 109 with squamous carcinoma (N1 = 21 and N2 = 11). PET/CT in the adenocarcinoma group had a sensitivity, specificity and accuracy of 53.8, 91.5 and 79.1%, and in the squamous cell group, of 87.5, 81.8 and 83.5%, respectively in a per-patient analysis. In the analysis for N2 disease on a per-patient basis, the sensitivity, specificity and accuracy were 38.8, 97.4, and 85.7% for the adenocarcinoma group and 81.8, 91.8 and 90.8% in the squamous cell group. In the adenocarcinoma group, the mean diameter of false-negative lymph nodes was 7 mm (standard deviation [SD] ± 2.5 mm) compared with the diameter of true-positive lymph nodes of 12.5 (SD ± 4 mm; P < 0.00001). In the squamous cell group, the mean diameter of false-negative lymph nodes was 7.4 mm (SD ± 2.8 mm) compared with the diameter of true-positive lymph nodes of 14.7 (SD ± 6 mm; P < 0.005). In the adenocarcinoma group, false-negative lymph nodes were statistically correlated with the presence of vascular invasion and in the squamous cell group only with the maximum standardized uptake value (SUVmax) < 5.4. CONCLUSIONS The sensitivity of PET/CT in detecting nodal metastasis in patients with adenocarcinoma is too low to avoid any further invasive staging procedure. Ultrasound-guided needle biopsy or mediastinoscopy is still necessary in staging patients undergoing lung resection for adenocarcinoma.