title: Intratumor Heterogeneity of ALK-Rearrangements and Homogeneity of EGFR-Mutations in Mixed Lung Adenocarcinoma.
abstract: BACKGROUND
  Non Small Cell Lung Cancer is a highly heterogeneous tumor. Histologic intratumor heterogeneity could be 'major', characterized by a single tumor showing two different histologic types, and 'minor', due to at least 2 different growth patterns in the same tumor. Therefore, a morphological heterogeneity could reflect an intratumor molecular heterogeneity. To date, few data are reported in literature about molecular features of the mixed adenocarcinoma. The aim of our study was to assess EGFR-mutations and ALK-rearrangements in different intratumor subtypes and/or growth patterns in a series of mixed adenocarcinomas and adenosquamous carcinomas.
  
  
  METHODS
  590 Non Small Cell Lung Carcinomas tumor samples were revised in order to select mixed adenocarcinomas with available tumor components. Finally, only 105 mixed adenocarcinomas and 17 adenosquamous carcinomas were included in the study for further analyses. Two TMAs were built selecting the different intratumor histotypes. ALK-rearrangements were detected through FISH and IHC, and EGFR-mutations were detected through IHC and confirmed by RT-PCR.
  
  
  RESULTS
  10/122 cases were ALK-rearranged and 7 from those 10 showing an intratumor heterogeneity of the rearrangements. 12/122 cases were EGFR-mutated, uniformly expressing the EGFR-mutated protein in all histologic components.
  
  
  CONCLUSIONS
  Our data suggests that EGFR-mutations is generally homogeneously expressed. On the contrary, ALK-rearrangement showed an intratumor heterogeneity in both mixed adenocarcinomas and adenosquamous carcinomas. The intratumor heterogeneity of ALK-rearrangements could lead to a possible impact on the therapeutic responses and the disease outcomes.
authors.affiliation: Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Zito Marino
authors.forename: Federica Zito
authors.initials: FZ
authors.lastname: Marino
authors.affiliation: Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Liguori
authors.affiliation: Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Aquino
authors.affiliation: Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Elvira
authors.initials: E
authors.lastname: La Mantia
authors.affiliation: Department of Pathophysiology and Organ Transplantation, University of Milan Medical School, Milan, Italy; Division of Pathology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico Milan, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Bosari
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milan Medical School, Milan, Italy; Division of Pathology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrero
authors.affiliation: Thoracic Surgery and Lung Transplantation Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Rosso
authors.affiliation: Department of Pathophysiology and Organ Transplantation, University of Milan Medical School, Milan, Italy; Division of Pathology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico Milan, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gaudioso
authors.affiliation: Department of Oncology and Anatomic Pathology, Hospital of National Relevance (AORN) Vincenzo Monaldi, Naples, Italy.
authors.forename: Nicla
authors.initials: N
authors.lastname: De Rosa
authors.affiliation: Biogem scarl, Institute for Genetic Research "Gaetano Salvatore", Ariano Irpino (Avellino), Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Scrima
authors.affiliation: Division of Thoracic Surgery, Department of Thoracic Surgical and Medical Oncology, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Martucci
authors.affiliation: Division of Thoracic Surgery, Department of Thoracic Surgical and Medical Oncology, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: La Rocca
authors.affiliation: Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Normanno
authors.affiliation: Medical Oncology Unit, Department of Thoracic Surgical and Medical Oncology, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Morabito
authors.affiliation: Division of Thoracic Surgery, Department of Thoracic Surgical and Medical Oncology, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Rocco
authors.affiliation: Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Botti
authors.affiliation: Pathology Unit, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS, Naples, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Franco
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases