title: Non-terminal respiratory unit type lung adenocarcinoma has three distinct subtypes and is associated with poor prognosis.
abstract: OBJECTIVE
  The characteristics of non-terminal respiratory unit (TRU) type lung adenocarcinoma are still unclear. The aim of the present study was to characterize non-TRU type lung adenocarcinoma.
  
  
  METHODS
  We analyzed the expression of mucins MUC5B and MUC5AC, as well as thyroid transcription factor-1 (TTF-1), using a tissue microarray comprising lung adenocarcinoma specimens from 244 consecutive patients. The presence of mutations in EGFR and KRAS were also determined.
  
  
  RESULTS
  TTF-1, MUC5B, and MUC5AC were detected in 219 (89.8%), 75 (30.7%), and 33 cases (13.5%), respectively. Cluster analysis of protein expression profiles and EGFR and KRAS mutations yielded five groups of tumors as follows: TRU1-type [TTF-1(+), MUC5B(-), MUC5AC(-), EGFR mutations(-)]; TRU2-type [TTF-1(+), MUC5B(-), MUC5AC(-), EGFR mutations(+)]; Combined-type [TTF-1(+), MUC5B(+), and/or MUC5AC(+)]; Bronchiolar-type [TTF-1(-), MUC5B(+) and/or MUC5AC(+)]; and Null-type [TTF-1(-), MUC5B(-), MUC5AC(-), EGFR mutations(-), KRAS mutations(-)]. TRU-type tumors, which include TRU1- and TRU2-type tumors, were significantly associated with TRU morphology, whereas Bronchiolar-type tumors were associated with non-TRU morphology. Combined-type cases exhibited intermediate morphologies between TRU-type and Bronchiolar-type cases. TRU-type was associated with significantly better prognosis, followed by Combined-type, Bronchiolar-type, and Null-type (disease-free survival [DFS] P = 0.017; overall survival [OS], P = 0.002). Multivariate analyses indicated that non-TRU type tumors, which include Bronchiolar-, Combined-, Null-type tumors, were significantly correlated with poorer prognoses for DFS (hazard ratio = 1.785; 95% CI, 1.041-3.063; P = 0.035) and OS (hazard ratio = 1.928; 95% CI, 1.084-3.421; P = 0.025).
  
  
  CONCLUSIONS
  This study revealed three distinct subtypes of non-TRU type adenocarcinomas. Additionally, non-TRU type tumors were associated with worse prognoses than TRU type tumors. The results presented here may be useful for select patients should appropriate therapies become available.
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Sumiyoshi
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan; Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan. Electronic address: akyoshi@shinshu-u.ac.jp.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshizawa
authors.affiliation: Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sonobe
authors.affiliation: Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Motoki
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Tsuruyama
authors.affiliation: Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Haga
mesh_terms: D000230:Adenocarcinoma / Q000145:classification* / Q000401:mortality / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000145:classification* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D055271:Mucin 5AC / Q000096:biosynthesis; D055257:Mucin-5B / Q000096:biosynthesis; D009154:Mutation; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D046888:Tissue Array Analysis; D014157:Transcription Factors; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C117307:KRAS protein, human; C524678:MUC5AC protein, human; C524578:MUC5B protein, human; D055271:Mucin 5AC; D055257:Mucin-5B; D011518:Proto-Oncogene Proteins; C504003:TTF1 protein, human; D014157:Transcription Factors; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: EGFR; KRAS; Lung adenocarcinoma; MUC5AC; MUC5B; Prognosis; Terminal respiratory unit (TRU)