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Recurrence of Urothelial Carcinoma of the Bladder: A Role for Insulin-Like Growth Factor-II Loss of Imprinting and Cytoplasmic E-Cadherin Immunolocalization

Authors' Affiliations: ¹ UCD School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland; ² UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland; ³ Department of Pathology, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland; ⁴ UCD School of Public Health and Population Science, University College Dublin, Belfield, Dublin, Ireland; ⁵ Department of Pathology, Mater Misericordiae Hospital, Dublin, Ireland; ⁶ School of Nursing, RCSI House, Royal College of Surgeons in Ireland, Dublin, Ireland; ⁷ Renal Unit, Beaumont Hospital, Dublin, Ireland; and ⁸ Department of Surgery, Mater Misericordiae Hospital, Dublin, Ireland

Requests for reprints: Amanda McCann, UCD School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland. Phone: 353-1-7166742; Fax: 353-1-7166888; E-mail: amanda.mccann{at}ucd.ie.

Purpose: This study documents the frequency of insulin-like growth factor-II (IGF-II) loss of imprinting (LOI) in a series of 87 bladder tissues. E-cadherin (CDH1) immunolocalization was also investigated due to the known redistribution of this adherence protein to the cytoplasm following exogenous exposure to IGF-II.

Experimental Design: Informative IGF-II cases were identified following DNA-PCR amplification and subsequent sequencing of the transcribable ApaI RFLP in exon 9 of IGF-II. Similar approaches using primer-specific cDNA templates identified the imprinting status of IGF-II in these informative cases. CDH1 cellular localization was assessed on a tissue microarray platform of 114 urothelial carcinoma of the bladder (UCB) cases (70 pT_a noninvasive and 44 pT₁ lamina propria invasive) using the commercially available Novocastra antibody.

Results: IGF-II LOI was evident in 7 of 17 (41%) UCB tumors and 4 of 11 (36%) tumor-associated normal urothelial samples. Two of four pT₁ grade 3 tumors, the subject of much debate concerning their suitability for radical cystectomy, showed LOI at the IGF-II locus. In those tumors showing IGF-II LOI, 4 of 7 (57%) displayed concomitant CDH1 cytoplasmic staining. In contrast, only 3 of 10 (30%) IGF-II maintenance of imprinting tumors had concomitant CDH1 cytoplasmic localization. UCB cell lines displaying cytoplasmic CDH1 immunolocalization expressed significantly higher levels of IGF-II (CAL29, HT1376, and RT112) compared with RT4, a cell line displaying crisp membranous CDH1 staining. Finally, cytoplasmic CDH1 staining was an independent predictor of a shorter time to recurrence independent of tumor grade and stage.

Conclusions: We suggest that CDH1 cytoplasmic immunolocalization as a result of increased IGF-II levels identifies those nonmuscle invasive presentations most likely to recur and therefore might benefit from more radical nonconserving bladder surgery.