title: Lack of NKX2.2 expression in bronchopulmonary typical carcinoid tumors: implications for patients with neuroendocrine tumor metastases and unknown primary site.
abstract: BACKGROUND
  Patients with neuroendocrine tumors (NETs) may have metastatic disease and unknown primary site. NETs commonly arise from the bronchopulmonary (BP) and gastrointestinal (GI) tract. The largest subgroups of well-differentiated BP-NETs are typical carcinoids (TCs). The homeodomain transcription factor NKX2.2 regulates development of gut serotonin cells and is a marker of GI-NETs. Previous work on a limited number of samples suggested that BP-TCs do not express NKX2.2. We hypothesized that lack of NKX2.2 expression in BP-TCs might be useful to distinguish BP- from GI-NETs, and evaluated NKX2.2 expression in a larger number of BP-TCs.
  
  
  METHODS
  Archived formalin-fixed, paraffin-embedded tissues were obtained from 13 previously undescribed patients with BP-TCs. Expression of NKX2.2, serotonin, and the NE marker chromogranin A (CgA) were assessed by immunohistochemistry.
  
  
  RESULTS
  CgA expression was robust in all 13 BP-TCs, confirming the NE phenotype. Serotonin expression was less frequent (9/13; 69%). Two patients with BP-TCs in which serotonin expression was absent exhibited Cushing's syndrome due to ectopic ACTH production. NKX2.2 expression was not observed in any of the 13 tumors.
  
  
  CONCLUSIONS
  Bronchopulmonary TCs uniformly express CgA but not NKX2.2. Because most of these tumors express serotonin, our findings suggest that NKX2.2 may not be required for serotonin production by BP-TCs. We conclude that the presence or absence of NKX2.2 expression may assist in the determination of the primary tumor site in patients with NET metastases of unknown origin. NET metastases that are CgA-positive/NKX2.2-negative would suggest a BP primary, whereas those that are CgA-positive/NKX2.2-positive would suggest a GI primary.
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143-1932, USA.
authors.forename: Yu-cheng
authors.initials: YC
authors.lastname: Wang
authors.forename: Gioia
authors.initials: G
authors.lastname: Iezza
authors.forename: Marlene B
authors.initials: MB
authors.lastname: Zuraek
authors.forename: David M
authors.initials: DM
authors.lastname: Jablons
authors.forename: Pierre R
authors.initials: PR
authors.lastname: Theodore
authors.forename: Emily K
authors.initials: EK
authors.lastname: Bergsland
authors.forename: David B
authors.initials: DB
authors.lastname: Donner
authors.forename: Robert S
authors.initials: RS
authors.lastname: Warren
authors.forename: Eric K
authors.initials: EK
authors.lastname: Nakakura
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002276:Carcinoid Tumor / Q000175:diagnosis / Q000378:metabolism*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins; D014157:Transcription Factors / Q000378:metabolism*; D055815:Young Adult; D029961:Zebrafish Proteins
chemical_list: D014408:Biomarkers, Tumor; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C000715631:NKX2-2 protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish