title: MicroRNA signature in thyroid fine needle aspiration cytology applied to "atypia of undetermined significance" cases.
abstract: BACKGROUND
  MicroRNA (miR) expression signatures are proposed to be able to differentiate thyroid cancer from benign thyroid lesions. We selected eight miRs (miR-146b, -221, -187, -197, -346, -30d, -138, and -302c) to examine the potential use of miRs to supplement diagnostic cytology in cases designated as "atypia of undetermined significance."
  
  
  METHODS
  miR expression was measured in thyroid fine needle aspiration (FNA) specimens by quantitative polymerase chain reaction. Gene expression analyses and linear discriminant analysis (LDA) were performed in a training sample set (n=60) to obtain a classification rule to predict FNA cases as benign or malignant. The predictions were cross-validated by comparing with the corresponding histological diagnoses. A validation sample set (n=68) was further tested with the established four-miR LDA classification rule.
  
  
  RESULTS
  A set of four miRs (miR-146b, -221, -187, and -30d) was identified that could differentiate malignant from benign lesions. A four-miR LDA classification rule was obtained and used to predict FNA cases as benign or malignant. For the training sample set, we obtained a diagnostic accuracy of 93.3%, sensitivity of 93.2%, specificity of 93.8%, positive predictive value (PPV) of 0.98, and negative predictive value (NPV) of 0.83. For the validation sample set, we obtained a diagnostic accuracy of 85.3%, sensitivity of 88.9%, specificity of 78.3%, PPV of 0.89, and NPV of 0.78. For the 30 atypia cases in the validation sample set, we obtained a diagnostic accuracy of 73.3%, sensitivity of 63.6%, specificity of 78.9%, PPV of 0.64, and NPV of 0.79. Based on the miR predictions, we classified the atypia cases predicted as "malignant" into "high risk" and those predicted as "benign" into "low risk" categories. While thyroid carcinomas, particularly papillary thyroid carcinomas (PTCs), were relatively enriched in the high-risk category, this particular miR panel is subject to inaccurate results in follicular neoplasias in atypia cases.
  
  
  CONCLUSIONS
  We demonstrate that miR amplification from FNA samples is feasible and that the particular four miR profile in this study can identify PTCs. However, further refinement is required for application to FNA cytology of "atypia of undetermined significance" cases due to low accuracy in classifying follicular neoplasias.
authors.affiliation: Department of Pathology, Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA. rulong.shen@osumc.edu
authors.forename: Rulong
authors.initials: R
authors.lastname: Shen
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Paul E
authors.initials: PE
authors.lastname: Wakely
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Saji
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nagy
authors.forename: Tisha
authors.initials: T
authors.lastname: Farrell
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ringel
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
authors.forename: Richard T
authors.initials: RT
authors.lastname: Kloos
authors.forename: Huiling
authors.initials: H
authors.lastname: He
mesh_terms: D044963:Biopsy, Fine-Needle; D002277:Carcinoma; D002291:Carcinoma, Papillary; D020869:Gene Expression Profiling; D006801:Humans; D035683:MicroRNAs / Q000032:analysis*; D058889:Molecular Typing / Q000379:methods*; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D016606:Thyroid Nodule / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D035683:MicroRNAs; C542542:MIRN146 microRNA, human; C525709:MIR221, human; C546086:MIRN30b microRNA, human