Chromatin phenotype karyometry can predict recurrence in papillary urothelial neoplasms of low malignant potential

Article type: Research Article

Authors: Montironi, Rodolfo^; | Scarpelli, Marina | Lopez-Beltran, Antonio | Mazzucchelli, Roberta | Alberts, David | Ranger-Moore, James | Bartels, Hubert G. | Hamilton, Peter W. | Einspahr, Janine | Bartels, Peter H.

Affiliations: Section of Pathological Anatomy and Histopathology, Polytechnic University of the Marche Region, Ancona, Italy | Unit of Anatomic Pathology, Cordoba University Medical School, Cordoba, Spain | College of Public Health, Arizona Cancer Center, University of Arizona, USA | The Queen's University, Belfast, Northern Ireland, UK

Note: [] Corresponding author: Prof. Rodolfo Montironi, Section of Pathological Anatomy and Histopathology, Polytechnic University of the Marche Region (Ancona), School of Medicine, United Hospitals, Via Conca, 71, I-60020 Torrette, Ancona, Italy. Fax: +39 071 889985; E-mail: [email protected].

Abstract: Background: A preceding exploratory study (J. Clin. Pathol. 57(2004), 1201–1207) had shown that a karyometric assessment of nuclei from papillary urothelial neoplasms of low malignant potential (PUNLMP) revealed subtle differences in phenotype which correlated with recurrence of disease. Aim of the study: To validate the results from the exploratory study on a larger sample size. Materials: 93 karyometric features were analyzed on haematoxylin and eosin-stained sections from 85 cases of PUNLMP. 45 cases were from patients who had a solitary PUNLMP lesion and were disease-free during a follow-up period of at least 8 years. The other 40 were from patients with a unifocal PUNLMP, with one or more recurrences in the follow-up. A combination of the previously defined classification functions together with a new P-index derived classification method was used in an attempt to classify cases and identify a biomarker of recurrence in PUNLMP lesions. Results: Validation was pursued by a number of separate approaches. First, the exact procedure from the exploratory study was applied to the large validation set. Second, since the discriminant function 2 of the exploratory study had been based on a small sample size, a new discriminant function was derived. The case classification showed a correct classification of 61% for non-recurrent and 74% for recurrent cases, respectively. Greater success was obtained by applying unsupervised learning technologies to take advantage of phenotypical composition (correct classification of 92%). This approach was validated by dividing the data into training and test sets with 2/3 of the cases assigned to the training sets, and 1/3 to the test sets, on a rotating basis, and validation of the classification rate was thus tested on three separate data sets by a leave-k-out process. The average correct classification was 92.8% (training set) and 84.6% (test set). Conclusions: Our validation study detected subvisual differences in chromatin organization state between non-recurrent and recurrent PUNLMP, thus allowing a very stable method of predicting recurrence of papillary urothelial neoplasms of low malignant potential by karyometry.

Keywords: Urothelium, papillary urothelial neoplasm of low malignant potential, recurrence

Journal: Analytical Cellular Pathology, vol. 29, no. 1, pp. 47-58, 2007