title: Morphological and genetic heterogeneity in multifocal lung adenocarcinoma: The case of a never-smoker woman.
abstract: Discrimination of multifocal primary lung cancers from lung metastases is crucial to allow for an appropriate clinical management. We report here a case of multifocal lung adenocarcinomas with different morphological and molecular patterns. Radical surgery of one lung nodule was performed at the time of diagnosis, and subsequently on two other lung nodules. At the time of distant relapse, biopsy was repeated for molecular characterization. The patient was treated with EGFR tyrosine kinase inhibitor according to the detection of EGFR exon 21 mutation in metastatic sample and in one of the three lung tumors, characterized by lower mutated allele frequency. The progression free survival was three months according to radiological criteria and the treatment was provided for six months, until clinical progression. Following the assessment of EGFR mutations by pyrosequencing, tumor samples were analyzed by a 30-gene next generation sequencing (NGS) panel, allowing to study intra- and inter-tumor heterogeneity and to confirm the three lung tumors as independent. Different molecular profiles of synchronous tumors and identical EGFR, PIK3CA and TP53 mutations in one of three primary lung tumors and the metachronous metastasis were identified. In conclusion, morphological and molecular characterization of multiple lung nodules by NGS may help to define synchronous and metachronous adenocarcinomas, thus affecting surgical indication and systemic treatment. Intratumor heterogeneity may be associated with differential sensitivity to targeted treatment.
authors.affiliation: Medical Oncology 2, Istituto Oncologico Veneto IRCCS, via Gattamelata 64, 35128 Padova, Italy. Electronic address: laura.bonanno@ioveneto.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Bonanno
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, University of Padova, via Giustiniani 2, 35128 Padova, Italy. Electronic address: fiorella.calabrese@unipd.it.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Calabrese
authors.affiliation: Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, via Gattamelata 64, 35128 Padova, Italy. Electronic address: giorgia.nardo@gmail.com.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Nardo
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, via Maroncelli 40, 47014 Meldola, FC, Italy. Electronic address: daniele.calistri@irst.emr.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Calistri
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, via Maroncelli 40, 47014 Meldola, FC, Italy. Electronic address: michela.tebaldi@irst.emr.it.
authors.forename: Michela
authors.initials: M
authors.lastname: Tebaldi
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, via Maroncelli 40, 47014 Meldola, FC, Italy. Electronic address: gianluca.tedaldi@irst.emr.it.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tedaldi
authors.affiliation: Medical Oncology 2, Istituto Oncologico Veneto IRCCS, via Gattamelata 64, 35128 Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, via Giustiniani 2, 35124 Padova, Italy. Electronic address: valentina.polo@ioveneto.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Polo
authors.affiliation: Department of Cardiothoracic and Vascular Sciences, University of Padova, via Giustiniani 2, 35128 Padova, Italy. Electronic address: stefvu@hotmail.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Vuljan
authors.affiliation: Medical Oncology 2, Istituto Oncologico Veneto IRCCS, via Gattamelata 64, 35128 Padova, Italy. Electronic address: adolfo.favaretto@ioveneto.it.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Favaretto
authors.affiliation: Medical Oncology 2, Istituto Oncologico Veneto IRCCS, via Gattamelata 64, 35128 Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, via Giustiniani 2, 35124 Padova, Italy. Electronic address: pierfranco.conte@unipd.it.
authors.forename: PierFranco
authors.initials: P
authors.lastname: Conte
authors.affiliation: Medical Oncology 2, Istituto Oncologico Veneto IRCCS, via Gattamelata 64, 35128 Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, via Giustiniani 2, 35124 Padova, Italy. Electronic address: albido@unipd.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Amadori
authors.affiliation: Thoracic Surgery Unit, Department of Cardiothoracic and Vascular Sciences, University of Padova, via Giustiniani 2, 35128 Padova, Italy. Electronic address: federico.rea@unipd.it.
authors.forename: Federico
authors.initials: F
authors.lastname: Rea
authors.affiliation: Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, via Gattamelata 64, 35128 Padova, Italy. Electronic address: stefano.indraccolo@unipd.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Indraccolo
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000368:Aged; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D009362:Neoplasm Metastasis; D009378:Neoplasms, Multiple Primary / Q000235:genetics / Q000473:pathology; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; Multifocal lung tumors; Mutate allele frequency; Next generation sequencing; Non-small cell lung cancer; Pathology