title: Cutaneous squamous cell carcinomas with markers of increased metastatic risk are associated with elevated numbers of neutrophils and/or granulocytic myeloid derived suppressor cells.
abstract: BACKGROUND
  A subset of presenting cutaneous squamous cell carcinomas (CSCC) is high risk with respect to their high rates of recurrence, metastasis and patient death. The identification of such high risk CSCC is problematic. Neutrophil and granulocytic myeloid derived suppressor cell (G-MDSC) numbers are elevated in a number of cancers, but their association with current markers of high risk tumors in the setting of CSCC is unknown.
  
  
  OBJECTIVE
  To assess circulating and tumor-localised neutrophil and G-MDSC populations for associations with high-risk tumor characteristics and overall survival (OS) in CSCC patients.
  
  
  METHODS
  A retrospective clinical audit was performed of patients who had hospital operations for primary CSCC and did not have other malignancies or HIV. Therapeutically immuno-suppressed individuals (TII, n=129) and non-TII (n=29) were analysed separately with respect to the presence of high-risk tumor features and OS. In addition, 47 patients with prospectively collected blood and primary CSCC tumor samples were analysed to determine frequencies of circulating G-MDSC and tumor localised CD66b+ and CD8+ leukocytes.
  
  
  RESULTS
  In the clinical audit of non-TII, high circulating neutrophil counts were associated with tumor thickness≥5mm, Clark level V and high T-stage. Univariate analysis showed elevated neutrophil count was a significant marker of poor OS, whilst tumor thickness remained the only independent histological predictor of OS after adjusting for age and immuno-suppression. The prospective study demonstrated that tumors≥5mm thick had significantly increased total and peri-tumorally localised CD66b+ leukocytes (comprising neutrophils and/or G-MDSC) and that elevated circulating G-MDSC numbers were associated with high T-stage tumors.
  
  
  CONCLUSIONS
  This study demonstrates that the presence of high risk CSCC is associated with increased numbers of both circulating and tumor resident populations of neutrophils and/or G-MDSC. These cell types therefore merit further investigation with respect to their functional and prognostic significance in CSCC.
authors.affiliation: Mackenzie Cancer Research Group, University of Otago Christchurch, PO Box 4345,Christchurch 8011, New Zealand; Centre for Free Radical Research, University of Otago Christchurch, PO Box 4345,Christchurch 8011, New Zealand.
authors.forename: Annika
authors.initials: A
authors.lastname: Seddon
authors.affiliation: Haematology Research Group, University of Otago Christchurch, PO Box 4345,Christchurch 8011, New Zealand.
authors.forename: Barry
authors.initials: B
authors.lastname: Hock
authors.affiliation: Department of Pathology, University of Otago Christchurch, PO Box 4345,Christchurch 8011, New Zealand.
authors.forename: Andrew
authors.initials: A
authors.lastname: Miller
authors.affiliation: Department of Plastic and Reconstructive Surgery, Canterbury District Health Board, Christchurch 8011, New Zealand.
authors.forename: Lukas
authors.initials: L
authors.lastname: Frei
authors.affiliation: Biostatistics and Computational Biology Unit, University of Otago Christchurch, PO Box 4345,Christchurch 8011, New Zealand.
authors.forename: John
authors.initials: J
authors.lastname: Pearson
authors.affiliation: Haematology Research Group, University of Otago Christchurch, PO Box 4345,Christchurch 8011, New Zealand.
authors.forename: Judith
authors.initials: J
authors.lastname: McKenzie
authors.affiliation: Department of Plastic and Reconstructive Surgery, Canterbury District Health Board, Christchurch 8011, New Zealand.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Simcock
authors.affiliation: Mackenzie Cancer Research Group, University of Otago Christchurch, PO Box 4345,Christchurch 8011, New Zealand; Department of Pathology, University of Otago Christchurch, PO Box 4345,Christchurch 8011, New Zealand. Electronic address: margaret.currie@otago.ac.nz.
authors.forename: Margaret
authors.initials: M
authors.lastname: Currie
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000032:analysis; D002452:Cell Count; D054869:Clinical Audit; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology*; D009367:Neoplasm Staging; D009504:Neutrophils / Q000276:immunology*; D011379:Prognosis; D011446:Prospective Studies; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000097:blood / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D016019:Survival Analysis
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules
keywords: Cutaneous squamous cell carcinoma; Granulocytic myeloid derived suppressor cell; Neutrophils; Tumor features