title: Molecular markers for reinforcement of histological subclassification of neuroendocrine lung tumors.
abstract: The degree of malignancy of neuroendocrine lung tumors (NEs) increases in this order: from typical carcinoids (TCs) through atypical carcinoids (ACs) to large cell neuroendocrine carcinomas (LCNECs) and small cell lung carcinomas (SCLCs). However, histological classification has sometimes proved difficult. We here investigated loss of heterozygosity (LOH) using eight microsatellite markers and expression of p53, Bcl-2 and Bax proteins using immunohistochemical methods in 57 NEs (19 TCs, 5 ACs, 14 LCNECs and 19 SCLCs), looking for objective genetic markers to distinguish between subtypes. The frequencies of LOHs on D3S1300, RBi2 and TP53, the combinations of LOH status for RBi2 and TP53, and the immunohistochemically demonstrated Bcl-2/Bax ratios and p53-positive rates significantly differed among histopathologically diagnosed NEs. Differentiation between TC and AC was possible with reference to LOH on D3S1300, RBi2 and TP53, and the combined LOH status on RBi2 and TP53 (i.e., both LOH(-) versus one LOH(+)). For comparison between AC and LCNEC + SCLC, LOH on TP53 or the combination of two markers--one LOH(+) versus both LOH(+)--was applied. Furthermore, in three discordant cases of diagnoses based on histology and LOH markers, diagnoses using the latter were considered to be more probable by survival analysis. The present study indicated that assessment of LOHs using microsatellite markers could provide objective markers that can distinguish subtypes of NEs, for which histological assessment may commonly result in disagreement.
authors.affiliation: Department of Pathology, Saitama Cancer Center, Kita-Adachi-gun, Saitama 362-0806, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Tokuchi
authors.forename: Takehisa
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Moriaki
authors.initials: M
authors.lastname: Hayashi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nishimura
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Ken
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Sato
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Eiju
authors.initials: E
authors.lastname: Tsuchiya
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D002276:Carcinoid Tumor / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000473:pathology; D018278:Carcinoma, Neuroendocrine / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D019254:Genes, bcl-2; D016158:Genes, p53; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000737:chemistry / Q000145:classification* / Q000235:genetics / Q000473:pathology; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis; D018358:Neuroendocrine Tumors / Q000737:chemistry / Q000145:classification* / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein