title: Prognostic factors in oral cavity and oropharyngeal squamous cell carcinoma.
abstract: BACKGROUND
  The survival of patients with head and neck squamous cell carcinoma (HNSCC) remains unaffected despite recent therapeutic advances. To reverse this trend, reliable and clinically applicable markers of tumor aggressiveness must be identified. One such marker may be the tumor-associated macrophage content. The authors hypothesized that tumor-associated macrophages contribute to HNSCC aggressiveness, and the objective of the current study was to prove this hypothesis using mRNA expression analysis and a large cohort of clinical specimens.
  
  
  METHODS
  Oligonucleotide microarray analysis was performed on a prospective cohort of 20 patients with previously untreated oral cavity or oropharynx squamous cell carcinoma (OC/OP SCCA) and on normal oropharyngeal mucosa from 4 patients. After determining whether macrophage chemoattractants were produced by tumors, conditioned media from three HNSCC cell lines were used to quantify macrophage migration in an in vitro assay. A high-density tissue microarray of 102 patients with previously untreated OC/OP SCCA was stained immunohistochemically for CD68 to identify tissue macrophages, and the results were correlated with clinicopathologic data and survival.
  
  
  RESULTS
  Monocyte chemoattractant protein 1 was up-regulated significantly in tumors compared with normal mucosa (P=0.0025; fold change=1.89). All University of Michigan SCC tumor cell line conditioned media caused a significant increase in macrophage migration (P <0.05). Tissue microarray data revealed that macrophage content of the primary tumor was associated strongly with lymph node metastasis (P <0.0001), extracapsular lymph node spread (P=0.0001), and advanced clinical disease stage (P=0.0002). When it was evaluated along with other clinicopathologic data, the macrophage content was found to be an independent predictor of lymph node metastasis (P <0.0001).
  
  
  CONCLUSIONS
  Primary tumor macrophage content is a strong predictor of tumor aggressiveness in HNSCC.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48103, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Marcus
authors.forename: Douglas
authors.initials: D
authors.lastname: Arenberg
authors.forename: Julia
authors.initials: J
authors.lastname: Lee
authors.forename: Celina
authors.initials: C
authors.lastname: Kleer
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Chepeha
authors.forename: Cecelia E
authors.initials: CE
authors.lastname: Schmalbach
authors.forename: Mozaffarul
authors.initials: M
authors.lastname: Islam
authors.forename: Supriti
authors.initials: S
authors.lastname: Paul
authors.forename: Quintin
authors.initials: Q
authors.lastname: Pan
authors.forename: Samir
authors.initials: S
authors.lastname: Hanash
authors.forename: Rork
authors.initials: R
authors.lastname: Kuick
authors.forename: Sofia D
authors.initials: SD
authors.lastname: Merajver
authors.forename: Theodoros N
authors.initials: TN
authors.lastname: Teknos
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000401:mortality; D045744:Cell Line, Tumor; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000032:analysis; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008264:Macrophages / Q000276:immunology*; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000276:immunology* / Q000401:mortality; D009361:Neoplasm Invasiveness; D009959:Oropharyngeal Neoplasms / Q000276:immunology* / Q000401:mortality; D010446:Peptide Fragments / Q000032:analysis; D011379:Prognosis; D011446:Prospective Studies; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018932:Chemokine CCL2; D010446:Peptide Fragments; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C106929:monocyte chemoattractant protein 1 (9-76)