title: Snail heterogeneity in clear cell renal cell carcinoma.
abstract: BACKGROUND
  Intratumor heterogeneity may be responsible of the unpredictable aggressive clinical behavior that some clear cell renal cell carcinomas display. This clinical uncertainty may be caused by insufficient sampling, leaving out of histological analysis foci of high grade tumor areas. Although molecular approaches are providing important information on renal intratumor heterogeneity, a focus on this topic from the practicing pathologist' perspective is still pending.
  
  
  METHODS
  Four distant tumor areas of 40 organ-confined clear cell renal cell carcinomas were selected for histopathological and immunohistochemical evaluation. Tumor size, cell type (clear/granular), Fuhrman's grade, Staging, as well as immunostaining with Snail, ZEB1, Twist, Vimentin, E-cadherin, β-catenin, PTEN, p-Akt, p110α, and SETD2, were analyzed for intratumor heterogeneity using a classification and regression tree algorithm.
  
  
  RESULTS
  Cell type and Fuhrman's grade were heterogeneous in 12.5 and 60 % of the tumors, respectively. If cell type was homogeneous (clear cell) then the tumors were low-grade in 88.57 % of cases. Immunostaining heterogeneity was significant in the series and oscillated between 15 % for p110α and 80 % for Snail. When Snail immunostaining was homogeneous the tumor was histologically homogeneous in 100 % of cases. If Snail was heterogeneous, the tumor was heterogeneous in 75 % of the cases. Average tumor diameter was 4.3 cm. Tumors larger than 3.7 cm were heterogeneous for Vimentin immunostaining in 72.5 % of cases. Tumors displaying negative immunostaining for both ZEB1 and Twist were low grade in 100 % of the cases.
  
  
  CONCLUSIONS
  Intratumor heterogeneity is a common event in clear cell renal cell carcinoma, which can be monitored by immunohistochemistry in routine practice. Snail seems to be particularly useful in the identification of intratumor heterogeneity. The suitability of current sampling protocols in renal cancer is discussed.
authors.affiliation: Department of Pathology, Cruces University Hospital, University of the Basque Country (UPV/EHU), Plaza de Cruces s/n, 48903, Barakaldo, Bizkaia, Spain. laura.zaldumbideduenas@osakidetza.eus.
authors.forename: Laura
authors.initials: L
authors.lastname: Zaldumbide
authors.affiliation: Quantitative Biomedicine Unit, Biocruces Health Research Institute, Barakaldo, Bizkaia, Spain. asier.erramuzpe@gmail.com.
authors.forename: Asier
authors.initials: A
authors.lastname: Erramuzpe
authors.affiliation: Department of Pathology, Complejo Hospitalario de Navarra-Hospital Virgen del Camino, Pamplona, Navarra, Spain. rosa.guarch.troyas@cfnavarra.es.
authors.forename: Rosa
authors.initials: R
authors.lastname: Guarch
authors.affiliation: Biomarkers in Cancer Unit, Biocruces Health Research Institute, Barakaldo, Bizkaia, Spain. rpulidomurillo@gmail.com.|Ikerbasque, Basque Foundation for Science, Bilbao, Bizkaia, Spain. rpulidomurillo@gmail.com.
authors.forename: Rafael
authors.initials: R
authors.lastname: Pulido
authors.affiliation: Quantitative Biomedicine Unit, Biocruces Health Research Institute, Barakaldo, Bizkaia, Spain. jesus.m.cortes@gmail.com.|Ikerbasque, Basque Foundation for Science, Bilbao, Bizkaia, Spain. jesus.m.cortes@gmail.com.|Department of Cell Biology and Histology, University of the Basque Country (UPV/EHU), 48940, Leioa, Spain. jesus.m.cortes@gmail.com.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Cortés
authors.affiliation: Department of Pathology, Cruces University Hospital, University of the Basque Country (UPV/EHU), Plaza de Cruces s/n, 48903, Barakaldo, Bizkaia, Spain. joseignacio.lopez@osakidetza.eus.|Biomarkers in Cancer Unit, Biocruces Health Research Institute, Barakaldo, Bizkaia, Spain. joseignacio.lopez@osakidetza.eus.
authors.forename: José I
authors.initials: JI
authors.lastname: López
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D000071250:Snail Family Transcription Factors / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D000071250:Snail Family Transcription Factors