p16(INK4a) expression in retinoblastoma: a marker of differentiation grade

Abstract

BACKGROUND: The tumor suppressor protein p16(INK4a) has been extensively studied in many tumors with very different results, ranging from its loss to its clear overexpression, which may be associated with degree of tumor differentiation and prognosis. However, its expression remains unclear in human retinoblastoma (RB), a common malignant tumor of retina in childhood. The aim of this study was to explore the expression pattern of p16(INK4a) in RB, and the correlation between p16(INK4a) expression and histopathological features of RB. METHODS: Sixty-five cases of RB were retrospectively analyzed. Paraffin-embedded blocks were retrieved from the archives of ocular pathology department at Zhongshan Ophthalmic Center of Sun Yat-sen University, China. Serial sections were cut and subjected to hematoxylin and eosin staining. Immunohistochemical staining was further done with antibodies p16(INK4a), CRX and Ki67. The correlation of p16 (INK4a) expression with CRX and Ki67 and clinicopathological features of RB were analyzed. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_180. RESULTS: RB tumor histologically consists of various differentiation components including undifferentiated (UD) cells, Homer-Wright rosettes (HWR) or Flexner-Winterstein rosettes (FWR) and fleurettes characteristic of photoreceptor differentiation or Retinocytoma (RC). p16(INK4a) expression was negative in both fleurette region and the residual retinal tissue adjacent to the tumor, weakly to moderately positive in FWR, strongly positive in both HWR and UD region. However, CRX had the reverse expression patterns in comparison with p16(INK4a). It was strongly positive in photoreceptor cells within the residual retina and fleurettes, but weakly to moderately positive in UD area. Together with Ki67 staining, high p16(INK4a) expression was associated with poor histological differentiation of RB tumors, which had higher risk features with the optic nerve invasion and uveal invasion. CONCLUSIONS: p16(INK4a) expression increased with the decreasing level of cell differentiation of RBs. RB tumors extensively expressing p16(INK4a) tended to have higher risk features with poor prognosis. This study suggested that p16(INK4a) would be a valuable molecular marker of RB to distinguish its histological phenotypes and to serve as a predictor of its prognosis.