title: Digital differentiation of non-small cell carcinomas of the lung by the fractal dimension of their epithelial architecture.
abstract: BACKGROUND
  In recent years, differences have emerged in the treatment of squamous and non-squamous non-small cell lung carcinomas (NSCLCs). This highlights the importance of accurate histopathologic classification. However, there remains inter-observer disagreement when making diagnoses based on histology. Fractal dimension (FD) is a mathematical measure of irregularity and complexity of shape. We hypothesize that the FD of carcinoma epithelial architecture can assist in differentiating adenocarcinoma (ADC) from squamous cell carcinoma (SCC) of the lung.
  
  
  METHODS
  134 resected (88 ADC and 46 SCC) cases of resected early-stage NSCLC were analyzed. Tissue micro arrays were generated from formalin-fixed paraffin-embedded tissue, stained with pan-cytokeratin, and digitally imaged and the FD of the epithelial structure calculated. Mean FD of ADC and SCC were compared using the independent t-test, partial correlations, and receiver operating characteristic (ROC) analyses.
  
  
  RESULTS
  A statistically significant difference (p<0.001) between the mean FD of ADC (M=1.70, SD=0.07) and SCC (M=1.78, SD=0.07) was found. Significance remained (p<0.001) when controlling for several possible confounders. ROC analysis demonstrated an area-under-the-curve of 0.81 (p<0.001).
  
  
  CONCLUSIONS
  The epithelial structure FD of NSCLC has potential as a reproducible and automated measure to help subtype NSCLCs into ADC and SCC. With further image analysis algorithm improvements, fractal analysis may be a component in computerized histomorphological assessments of lung cancer and may provide an adjunct test in differentiating NSCLCs.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary, 1403 29 Street NW, Calgary, AB, Canada T2N 2T9.
authors.forename: Lik Hang
authors.initials: LH
authors.lastname: Lee
authors.affiliation: Department of Physics and Astronomy, University of Calgary, 2500 University Drive NW, Calgary, AB, Canada T2N 1N4; Department of Oncology, University of Calgary and Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, AB, Canada T2 N 4N2.
authors.forename: Mauro
authors.initials: M
authors.lastname: Tambasco
authors.affiliation: Department of Oncology, University of Calgary and Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, AB, Canada T2 N 4N2.
authors.forename: Shannon
authors.initials: S
authors.lastname: Otsuka
authors.affiliation: Department of Oncology, University of Calgary and Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, AB, Canada T2 N 4N2.
authors.forename: Allison
authors.initials: A
authors.lastname: Wright
authors.affiliation: Functional Tissue Imaging Unit, Translational Research Laboratory, Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, AB, Canada T2 N 4N2.
authors.forename: Alexander
authors.initials: A
authors.lastname: Klimowicz
authors.affiliation: Functional Tissue Imaging Unit, Translational Research Laboratory, Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, AB, Canada T2 N 4N2.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Petrillo
authors.affiliation: Department of Oncology, University of Calgary and Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, AB, Canada T2 N 4N2.
authors.forename: Don
authors.initials: D
authors.lastname: Morris
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary, 1403 29 Street NW, Calgary, AB, Canada T2N 2T9; Department of Physics and Astronomy, University of Calgary, 2500 University Drive NW, Calgary, AB, Canada T2N 1N4.
authors.forename: Anthony
authors.initials: A
authors.lastname: Magliocco
authors.affiliation: Department of Oncology, University of Calgary and Tom Baker Cancer Centre, 1331 29 Street NW, Calgary, AB, Canada T2 N 4N2. Electronic address: Gwyn.Bebb@albertahealthservices.ca.
authors.forename: D Gwyn
authors.initials: DG
authors.lastname: Bebb
mesh_terms: D000230:Adenocarcinoma / Q000648:ultrastructure; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000648:ultrastructure*; D005260:Female; D017709:Fractals; D006801:Humans; D007091:Image Processing, Computer-Assisted; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000175:diagnosis / Q000648:ultrastructure*; D008297:Male; D008875:Middle Aged; D020545:Respiratory Mucosa / Q000648:ultrastructure*; D012680:Sensitivity and Specificity
keywords: Carcinoma; Digital imaging; Digital microscopy; Fractal analysis; Histology; Lung