Telomere shortening distinguishes inverted urothelial neoplasms Sean R Williamson, 1 Shaobo Zhang, 1 Antonio Lopez-Beltran, 2 Rodolfo Montironi, 3 Mingsheng Wang 1 & Liang Cheng 1,4 1 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA, 2 Department of Pathology, Cordoba University, Cordoba, Spain, 3 Institute of Pathological Anatomy and Histopathology, School of Medicine, Polytechnic University of the Marche Region (Ancona), United Hospitals, Ancona, Italy, and 4 Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA Date of submission 1 August 2012 Accepted for publication 14 September 2012 Published online Article Accepted 17 September 2012 Williamson S R, Zhang S, Lopez-Beltran A, Montironi R, Wang M & Cheng L (2013) Histopathology Telomere shortening distinguishes inverted urothelial neoplasms Aims: To investigate relative telomere length in inverted urothelial neoplasms, including inverted pap- illoma and urothelial carcinoma with an inverted growth pattern. Telomere shortening has been impli- cated as an early event in the development of epithe- lial malignancies in a number of organ systems. Methods and results: Formalin-fixed, paraffin-embed- ded tissue sections from 77 cases were studied, including 26 cases of inverted papilloma, 26 urotheli- al carcinomas with inverted growth, and 25 cases of cystitis glandularis. Quantitative fluorescence in-situ hybridization (FISH) was performed on interphase nuclei, utilizing a telomere-specific peptide nucleic acid probe to assess telomeric signal intensity. Rela- tive telomere lengths for urothelial carcinoma with inverted growth, cystitis glandularis and inverted papilloma were 29%, 84%, and 91%, respectively. A statistically significant reduction in relative telomere length was present between urothelial carcinoma with inverted growth and inverted papilloma (P < 0.001); no significant difference was detected between normal urothelium, cystitis glandularis, and inverted papilloma. Conclusions: Significant telomere shortening in uro- thelial carcinoma with inverted growth as compared with inverted papilloma distinguishes the two lesions, and supports the notion that inverted papilloma is a benign neoplasm with a distinct pathogenetic mecha- nism of development. Telomeric FISH analysis may be a useful biomarker in distinguishing inverted papil- loma from urothelial carcinoma with inverted growth. Keywords: biomarker, cystitis glandularis, fluorescence in-situ hybridization (FISH), inverted papilloma, telomere, urinary bladder, urothelial carcinoma with inverted growth Introduction Inverted papilloma of the urinary bladder is an uncommon epithelial neoplasm that is generally con- sidered to be benign, 1–8 although some controversy exists with regard to its potential for aggressive behaviour. With traditional light microscopic diagnos- tic methods, these lesions are characterized histologi- cally by thin interanastomosing cords of urothelial cells that invaginate into the underlying lamina pro- pria, sometimes showing a similar appearance to florid von Brunn nests or cystitis cystica/glandularis of the usual type. 8 Mimicking inverted papilloma, urothelial carcinoma occasionally shows a similar pattern of inverted growth, 9 usually in concert with a greater degree of cytological atypia and distinct Address for correspondence: Liang Cheng, MD, Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 West 11th Street, IU Health Pathology Laboratory Room 4010, Indianapolis, IN 46202, USA. e-mail: lcheng@iupui.edu © 2012 Blackwell Publishing Limited. Histopathology 2013 DOI: 10.1111/his.12030