P16(INK4a) expression in retinoblastoma: a marker of differentiation grade.

Yue Liu,Ping Zhang,Shangtao Wan,Wenxin Zhang,Yongping Li,Jianxian Lin,Xiufeng Zhong

doi:10.1186/s13000-014-0180-1

Abstract

BackgroundThe tumor suppressor protein p16INK4a 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 p16INK4a in RB, and the correlation between p16INK4a expression and histopathological features of RB.MethodsSixty-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 p16INK4a, CRX and Ki67. The correlation of p16 INK4a expression with CRX and Ki67 and clinicopathological features of RB were analyzed.ResultsRB 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). p16INK4a 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 p16INK4a. 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 p16INK4a expression was associated with poor histological differentiation of RB tumors, which had higher risk features with the optic nerve invasion and uveal invasion.Conclusionsp16INK4a expression increased with the decreasing level of cell differentiation of RBs. RB tumors extensively expressing p16INK4a tended to have higher risk features with poor prognosis. This study suggested that p16INK4a would be a valuable molecular marker of RB to distinguish its histological phenotypes and to serve as a predictor of its prognosis.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_180

Highlights

The tumor suppressor protein p16INK4a 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
Our results demonstrated that p16INK4a expression increased with the dedifferentiation of RB, showing strongly positive in undifferentiated cells and Homer-Wright rosettes (HWR), weakly to moderately positive in Flexner-Winterstein rosettes (FWR), but negative in well-differentiated cells with fleurettes
The tumor samples were divided into four groups according to the level of cell differentiation: undifferentiated (UD) group predominantly consisting of undifferentiated tumor cells and pseudorosettes; HWR or FWR group in which rosettes accounted for over 70% of the lesion according to the predominant rosette phenotype; and RC group in which fleurettes characteristic of photoreceptor differentiation accounted for over 60% of the lesion [1,2]

Summary

Introduction

The tumor suppressor protein p16INK4a 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. Retinoblastoma (RB), the most common primary malignant intraocular tumor in childhood, has different pathological phenotypes from undifferentiated tumor cells, Homer-Wright rosettes (HWR) or Flexner-Winterstein rosettes(FWR) to fleurettes. These phenotypes reflect to some extent the level of tumor differentiation which is a key factor in grade of retinoblastoma and prediction of its prognosis [1,2]. Retinocytoma (RC), called retinoma, has been proposed to be the benign variant of RB since it is largely composed of benignappearing cells with elongated eosinophilic fleurettes similar to the inner segment of photoreceptor cells and because it has better prognosis than RB in general [3,4,5] These components with various degree of differentiation have been a challenge to be morphologically identified by researchers, sometimes even by experienced pathologists.

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