title: Circulating Myeloid-Derived Suppressor Cells Predict Differentiated Thyroid Cancer Diagnosis and Extent.
abstract: BACKGROUND
  Establishing the preoperative diagnosis and long-term prognosis of differentiated thyroid cancer (DTC) remain challenging in some patients. Myeloid-derived suppressor cells (MDSC) are tumor-induced cells mediating immune tolerance that are detectable in the peripheral blood of cancer patients. The authors previously developed a novel clinical assay to detect the phenotypes of two human MDSC subsets in peripheral blood, and hypothesize that higher MDSC levels measured by this assay correlate positively with both malignancy and worse patient outcomes.
  
  
  METHODS
  A prospective observational pilot study was performed of patients undergoing thyroidectomy for a solitary thyroid nodule. The presence of a thyroid nodule >1 cm was confirmed sonographically, and fine-needle aspiration biopsy performed prior to surgery in all cases. Peripheral blood collected preoperatively was analyzed using a novel flow cytometry-based immunoassay to detect and quantify two subsets of human MDSC. Circulating MDSC levels were compared by histopathologic diagnosis, stage, and presence of persistent disease after treatment.
  
  
  RESULTS
  Of 50 patients included in this study, MDSC measurement was successful in 47 (94%). One patient was found to have a concurrent cancer, leaving 46 patients for primary analysis. The cytologic diagnoses were benign in five (10.8%), atypia or follicular lesion of undetermined significance in five (10.8%), suspicious for follicular neoplasm in five (10.8%), suspicious for malignant in three (6.5%), and malignant in 28 (60.1%) of the 46 nodules. Final histopathology was benign in 11 (24%) and DTC in 35 (76%), encompassing 34 PTC cases and one follicular thyroid carcinoma. Mean percentages of CD11b(+)HLA-DR(low)HIF1a(+) MDSC (CD11b(+)MDSC) were 14.0 ± 6.2% and 7.9 ± 3.6% in DTC versus benign nodules, respectively (p < 0.005). A cutoff of 12% yielded a specificity of 0.91, a sensitivity of 0.72, and a likelihood ratio of 7.9. Mean CD11b(+)MDSC levels increased linearly with higher TNM stage (p < 0.01), and were 19.4 ± 5.4 in patients with persistent cancer after surgery compared with 13.2 ± 6.8 in those without evidence of disease (p < 0.05).
  
  
  CONCLUSIONS
  MDSC measurement using this flow cytometry-based assay represents a novel approach for preoperatively assessing malignancy risk and cancer extent in patients with thyroid nodules. While further validation is needed, these data suggest that MDSC assessment may serve as a useful adjunct when cytology is indeterminate, and predict tumor stage and recurrence risk in cases of thyroid cancer.
authors.affiliation: 1 Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital , Boston, Massachusetts.
authors.forename: Trevor E
authors.initials: TE
authors.lastname: Angell
authors.affiliation: 2 Department of Medicine, Brigham and Women's Hospital , Boston, Massachusetts.
authors.forename: Melissa G
authors.initials: MG
authors.lastname: Lechner
authors.affiliation: 3 Department of Pathology, Keck School of Medicine, University of Southern California , Los Angeles, California.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Smith
authors.affiliation: 3 Department of Pathology, Keck School of Medicine, University of Southern California , Los Angeles, California.
authors.forename: Sue E
authors.initials: SE
authors.lastname: Martin
authors.affiliation: 4 Department of Biostatistics, Keck School of Medicine, University of Southern California , Los Angeles, California.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Groshen
authors.affiliation: 5 Department of Otolaryngology, Keck School of Medicine, University of Southern California , Los Angeles, California.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Maceri
authors.affiliation: 6 Department of Endocrinology, Keck School of Medicine, University of Southern California , Los Angeles, California.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Singer
authors.affiliation: 3 Department of Pathology, Keck School of Medicine, University of Southern California , Los Angeles, California.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Epstein
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood; D044963:Biopsy, Fine-Needle; D002454:Cell Differentiation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping / Q000379:methods; D008297:Male; D008875:Middle Aged; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology*; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D010641:Phenotype; D010865:Pilot Projects; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012307:Risk Factors; D013964:Thyroid Neoplasms / Q000097:blood / Q000175:diagnosis / Q000276:immunology* / Q000601:surgery; D016606:Thyroid Nodule / Q000097:blood / Q000175:diagnosis / Q000276:immunology* / Q000601:surgery; D013965:Thyroidectomy; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor