Small-cell carcinoma in the setting of pulmonary adenocarcinoma: new insights in the era of molecular pathology.
BACKGROUND
Transformation into small-cell lung carcinoma (SCLC) has been reported as an evolution of lung adenocarcinoma acquiring resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). However, spontaneous association of SCLC and adenocarcinoma also exists. We sought to compare patients' clinical features and mutation status of EGFR in each tumor component in these conditions.


METHODS
Our study is based on nine consecutive cases of SCLC, occurring synchronously or after a previous diagnosis of pulmonary adenocarcinoma, with or without TKI-based therapy, diagnosed in Marie Lannelongue Surgical Center, France, between 2001 and 2013. Molecular analysis by DNA direct sequencing was performed to detect EGFR mutations on formalin-fixated tissue mostly from surgically resected tumors.


RESULTS
Six patients had a metachronous occurrence of SCLC after adenocarcinoma (2 after TKI); three had a synchronous form. There were four combined SCLCs/adenocarcinomas. Seven adenocarcinoma components were EGFR mutated: five exon 19 deletions and two mutations in exon 21 (L833_V834delinsFL and L858R). Four SCLC components were EGFR mutated. Two cases occurred in never-smoker women with adenocarcinoma treated with TKI: one with E872 mutation in exon 21 and one combined SCLC/adenocarcinoma with exon 19 deletion in both components. Two cases were spontaneous: a SCLC with exon 19 deletion occurring after a nonmutated adenocarcinoma and a combined SCLC/adenocarcinoma with exon 21 mutation (L833_V834delinsFL) in both components.


CONCLUSIONS
SCLC developing in association with adenocarcinoma, either synchronously or metachronously, seem linked to EGFR mutation, regardless of TKI use. Our findings suggest that such associated cases should be tested for EGFR mutations.
*Department of Pathology, Institut d'Oncologie Thoracique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France; †Department of Medical Biology and Pathology; ‡Department of Oncology, Institut d'Oncologie Thoracique, Institut Gustave Roussy, Villejuif, France; and §Department of Thoracic and Vascular Surgery, Institut d'Oncologie Thoracique, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
Emma
E
Norkowski
Maria-Rosa
MR
Ghigna
Ludovic
L
Lacroix
Thierry
T
Le Chevalier
Élie
É
Fadel
Philippe
P
Dartevelle
Peter
P
Dorfmuller
Vincent
V
Thomas de Montpréville
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D000368:Aged; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D009378:Neoplasms, Multiple Primary / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D016609:Neoplasms, Second Primary / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D011379:Prognosis; D055752:Small Cell Lung Carcinoma / Q000235:genetics / Q000473:pathology* / Q000601:surgery
C512478:EGFR protein, human; D066246:ErbB Receptors