title: Clinicopathological significance of cancer stem-like cell markers in high-grade neuroendocrine carcinoma of the lung.
abstract: OBJECTIVE
  This study aimed to evaluate the clinicopathological significance of cancer stem-like cell (CSLC) markers in high-grade neuroendocrine carcinoma (HGNEC) of the lung, including small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC).
  
  
  METHODS
  We retrospectively studied patients who underwent surgical resection of SCLC (n = 60) and LCNEC (n = 45) to analyze their clinicopathological profiles and the immunohistochemical expression of putative CSLC markers (Caveolin, Notch, CD44, CD166, SOX2, ALDH1, and Musashi1). Staining scores for these markers in tumor cells were calculated by multiplying the percentage of positive tumor cells per lesion by the staining intensity level (0, 1, and 2); a score of ≥ 10 represented positive expression.
  
  
  RESULTS
  There was a difference between SCLC and LCNEC with respect to both SOX2 (55 vs. 27 %, p = 0.003) and CD166 (27 vs. 47 %, p = 0.034) expression. ALDH1 expression was equally observed in SCLC and LCNEC (67 vs. 73 %, p = 0.46), and patients with ALDH1-positive HGNEC had significantly worse recurrence-free survival (RFS) and overall survival (OS) rates than those with ALDH1-negative HGNEC (5-year RFS: 39 vs. 67 %, p = 0.009; 5-year OS: 50 vs. 79 %, p = 0.021). A multivariate analysis revealed that positive ALDH1 expression was an independent unfavorable prognostic factor with respect to both RFS and OS.
  
  
  CONCLUSIONS
  The differences in the expression profiles of CSLC markers might reflect morphological differences between SCLC and LCNEC. Positive ALDH1 expression in lung HGNEC was associated with an unfavorable patient prognosis, which suggested that ALDH1-positive tumor cells might be future therapeutic targets for the treatment of lung HGNEC.
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.|Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Morise
authors.affiliation: Department of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. thishida@east.ncc.go.jp.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Hishida
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Department of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Yoshida
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.|Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ohe
authors.affiliation: Department of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Kanji
authors.initials: K
authors.lastname: Nagai
authors.affiliation: Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Genichiro
authors.initials: G
authors.lastname: Ishii
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018287:Carcinoma, Large Cell / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D018278:Carcinoma, Neuroendocrine / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D012189:Retrospective Studies; D055752:Small Cell Lung Carcinoma / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor
keywords: Aldehyde dehydrogenase 1 (ALDH1); Cancer stem-like cells; High-grade neuroendocrine carcinoma; Large cell neuroendocrine carcinoma; Small cell lung carcinoma