• Department of Clinical and Experimental Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy; Division of Cancer Epidemiology (C020), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: mario.mascalchi@unifi.it.
• Clinical Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy.
• Department of Radiology, Emergency Radiology AOU Careggi, Florence, Italy.
• Division of Cancer Epidemiology (C020), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
• Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy; Pulmonary Unit, Cardiothoracic and Vascular Department, Pisa University Hospital, Pisa, Italy.
• Division of Radiology (E010), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
• Radiologia, Villa Erbosa, Gruppo San Donato, Bologna, Italy.
• Department of Electrical, Electronic, and Information Engineering "Guglielmo Marconi", University of Bologna, Cesena, Italy.
• Department of Experimental and Clinical Medicine, University of Florence, Italy.
• Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Italy.

PURPOSE: To investigate the early radiological features and survival of Large Cell Carcinoma (LCC) cases diagnosed in low-dose computed tomography (LDCT) screening trials.

METHODS: Two radiologists jointly reviewed the radiological features of screen-detected LCCs observed in NLST, ITALUNG, and LUSI trials between 2002 and 2016, comprising a total of 29,744 subjects who underwent 3-5 annual screening LDCT examinations. Survival or causes of death were established according to the mortality registries extending more than 12 years since randomization.

RESULTS: LCC was diagnosed in 30 (4 %) of 750 subjects with screen-detected lung cancer (LC), including 15 prevalent and 15 incident cases. Three additional LCCs occurred as interval cancers during the screening period. LDCT images were available for 29 cases of screen-detected LCCs, and 28 showed a single, peripheral, and well-defined solid nodule or mass with regularly smooth (39 %), lobulated (43 %), or spiculated (18 %) margins. One case presented as hilar mass. In 9 incident LCCs, smaller solid nodules were identified in prior LDCT examinations, allowing us to calculate a mean Volume Doubling Time (VDT) of 98.7 ± 47.8 days. The overall five-year survival rate was 50 %, with a significant (p = 0.0001) difference between stages I-II (75 % alive) and stages III-IV (10 % alive).

CONCLUSIONS: LCC is a fast-growing neoplasm that can escape detection by annual LDCT screening. LCC typically presents as a single solid peripheral nodule or mass, often with lobulated margins, and exhibits a short VDT. The 5-year survival reflects the stage at diagnosis.