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Diagnostic Pathology
Published in: Diagnostic Pathology 1/2014

Open Access 01-12-2014 | Research

p16INK4a expression in retinoblastoma: a marker of differentiation grade

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

Published in: Diagnostic Pathology | Issue 1/2014

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Abstract

Background

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. 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.

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 p16INK4a, CRX and Ki67. The correlation of p16 INK4a expression with CRX and Ki67 and clinicopathological features of RB were analyzed.

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). 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.

Conclusions

p16INK4a 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 Slides

The virtual slide(s) for this article can be found here: http://​www.​diagnosticpathol​ogy.​diagnomx.​eu/​vs/​13000_​2014_​180
Appendix
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Literature
1.
Kashyap S, Sethi S, Meel R, Pushker N, Sen S, Bajaj MS, Chandra M, Ghose S: A histopathologic analysis of eyes primarily enucleated for advanced intraocular retinoblastoma from a developing country. Arch Pathol Lab Med. 2012, 136: 190-193. 10.5858/arpa.2010-0759-OA.PubMedCrossRef
2.
Suryawanshi P, Ramadwar M, Dikshit R, Kane SV, Kurkure P, Banavali S, Viswanathan S: A study of pathologic risk factors in postchemoreduced, enucleated specimens of advanced retinoblastomas in a developing country. Arch Pathol Lab Med. 2011, 135: 1017-1023. 10.5858/2010-0311-OAR2.PubMedCrossRef
3.
Gallie BL, Ellsworth RM, Abramson DH, Phillips RA: Retinoma: spontaneous regression of retinoblastoma or benign manifestation of the mutation?. Br J Cancer. 1982, 45: 513-521. 10.1038/bjc.1982.87.PubMedPubMedCentralCrossRef
4.
Dimaras H, Khetan V, Halliday W, Orlic M, Prigoda NL, Piovesan B, Marrano P, Corson TW, Eagle RC, Squire JA, Gallie BL: Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma. Hum Mol Genet. 2008, 17: 1363-1372. 10.1093/hmg/ddn024.PubMedCrossRef
5.
Eagle RC: High-risk features and tumor differentiation in retinoblastoma: a retrospective histopathologic study. Arch Pathol Lab Med. 2009, 133: 1203-1209.PubMed
6.
Witkiewicz AK, Knudsen KE, Dicker AP, Knudsen ES: The meaning of p16(ink4a) expression in tumors: functional significance, clinical associations and future developments. Cell Cycle. 2011, 10: 2497-2503. 10.4161/cc.10.15.16776.PubMedPubMedCentralCrossRef
7.
Courtois-Cox S, Genther Williams SM, Reczek EE, Johnson BW, McGillicuddy LT, Johannessen CM, Hollstein PE, MacCollin M, Cichowski K: A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell. 2006, 10: 459-472. 10.1016/j.ccr.2006.10.003.PubMedPubMedCentralCrossRef
8.
Hilliard NJKD, Sellheyer K: p16 expression differentiates between desmoplastic Spitz nevus and desmoplastic melanoma. J Cutan Pathol. 2009, 36: 753-759. 10.1111/j.1600-0560.2008.01154.x.PubMedCrossRef
9.
Lam AK, Ong K, Giv MJ, Ho YH: p16 expression in colorectal adenocarcinoma: marker of aggressiveness and morphological types. Pathology. 2008, 40: 580-585. 10.1080/00313020802320713.PubMedCrossRef
10.
Garcia V, Silva J, Dominguez G, Garcia JM, Pena C, Rodriguez R, Provencio M, Espana P, Bonilla F: Overexpression of p16INK4a correlates with high expression of p73 in breast carcinomas. Mutat Res. 2004, 554: 215-221. 10.1016/j.mrfmmm.2004.04.008.PubMedCrossRef
11.
Ivanova TA, Golovina DA, Zavalishina LE, Volgareva GM, Katargin AN, Andreeva YY, Frank GA, Kisseljov FL, Kisseljova NP: Up-regulation of expression and lack of 5’ CpG island hypermethylation of p16 INK4a in HPV-positive cervical carcinomas. BMC Cancer. 2007, 7: 47-10.1186/1471-2407-7-47.PubMedPubMedCentralCrossRef
12.
Xu R, Wang F, Wu L, Wang J, Lu C: A systematic review of hypermethylation of p16 gene in esophageal cancer. Cancer Biomark. 2013, 13: 215-226.PubMed
13.
Indovina P, Acquaviva A, De Falco G, Rizzo V, Onnis A, Luzzi A, Giorgi F, Hadjistilianou T, Toti P, Tomei V, Pentimalli F, Carugi A, Giordano A: Downregulation and aberrant promoter methylation of p16INK4A: a possible novel heritable susceptibility marker to retinoblastoma. J Cell Physiol. 2010, 223: 143-150.PubMed
14.
Coupland SE, Bechrakis N, Schuler A, Anagnostopoulos I, Hummel M, Bornfeld N, Stein H: Expression patterns of cyclin D1 and related proteins regulating G1-S phase transition in uveal melanoma and retinoblastoma. Br J Ophthalmol. 1998, 82: 961-970. 10.1136/bjo.82.8.961.PubMedPubMedCentralCrossRef
15.
Nishida A, Furukawa A, Koike C, Tano Y, Aizawa S, Matsuo I, Furukawa T: Otx2 homeobox gene controls retinal photoreceptor cell fate and pineal gland development. Nat Neurosci. 2003, 6: 1255-1263. 10.1038/nn1155.PubMedCrossRef
16.
Glubrecht DD, Kim JH, Russell L, Bamforth JS, Godbout R: Differential CRX and OTX2 expression in human retina and retinoblastoma. J Neurochem. 2009, 111: 250-263. 10.1111/j.1471-4159.2009.06322.x.PubMedPubMedCentralCrossRef
17.
Terry J, Calicchio ML, Rodriguez-Galindo C, Perez-Atayde AR: Immunohistochemical expression of CRX in extracranial malignant small round cell tumors. Am J Surg Pathol. 2012, 36: 1165-1169. 10.1097/PAS.0b013e3182601d84.PubMedCrossRef
18.
Zhao P, Hu YC, Talbot IC: Expressing patterns of p16 and CDK4 correlated to prognosis in colorectal carcinoma. World J Gastroenterol. 2003, 9: 2202-2206.PubMedPubMedCentralCrossRef
19.
Canadian Retinoblastoma Society: National retinoblastoma StrategyCanadian guidelines for care. Can J Ophthalmol. 2009, 44 (Suppl 2): S1-S88.
20.
Linn Murphree A: Intraocular retinoblastoma: the case for a new group classification. Ophthalmol Clin North Am. 2005, 18: 41-53. 10.1016/j.ohc.2004.11.003. viiiPubMedCrossRef
21.
Schwartz B, Avivi-Green C, Polak-Charcon S: Sodium butyrate induces retinoblastoma protein dephosphorylation, p16 expression and growth arrest of colon cancer cells. Mol Cell Biochem. 1998, 188: 21-30. 10.1023/A:1006831330340.PubMedCrossRef
22.
Romagosa C, Simonetti S, Lopez-Vicente L, Mazo A, Lleonart ME, Castellvi J, Ramon y Cajal S: p16(Ink4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene. 2011, 30: 2087-2097. 10.1038/onc.2010.614.PubMedCrossRef
23.
Di Vinci A, Perdelli L, Banelli B, Salvi S, Casciano I, Gelvi I, Allemanni G, Margallo E, Gatteschi B, Romani M: p16(INK4a) promoter methylation and protein expression in breast fibroadenoma and carcinoma. Int J Cancer. 2005, 114: 414-421. 10.1002/ijc.20771.PubMedCrossRef
24.
Zhao P, Mao X, Talbot IC: Aberrant cytological localization of p16 and CDK4 in colorectal epithelia in the normal adenoma carcinoma sequence. World J Gastroenterol. 2006, 12: 6391-6396.PubMedPubMedCentral
25.
Souza-Rodrigues E, Estanyol JM, Friedrich-Heineken E, Olmedo E, Vera J, Canela N, Brun S, Agell N, Hubscher U, Bachs O, Jaumot M: Proteomic analysis of p16ink4a-binding proteins. Proteomics. 2007, 7: 4102-4111. 10.1002/pmic.200700133.PubMedCrossRef
26.
Shen WW, Wu J, Cai L, Liu BY, Gao Y, Chen GQ, Fu GH: Expression of anion exchanger 1 sequestrates p16 in the cytoplasm in gastric and colonic adenocarcinoma. Neoplasia. 2007, 9: 812-819. 10.1593/neo.07403.PubMedPubMedCentralCrossRef
27.
Mills IG: Nuclear translocation and functions of growth factor receptors. Semin Cell Dev Biol. 2012, 23: 165-171. 10.1016/j.semcdb.2011.09.004.PubMedCrossRef
28.
Sastre X, Chantada GL, Doz F, Wilson MW, de Davila MT, Rodriguez-Galindo C, Chintagumpala M, Chevez-Barrios P, International Retinoblastoma Staging Working G: Proceedings of the consensus meetings from the International Retinoblastoma Staging Working Group on the pathology guidelines for the examination of enucleated eyes and evaluation of prognostic risk factors in retinoblastoma. Arch Pathol Lab Med. 2009, 133: 1199-1202.PubMed
Metadata
Title
p16INK4a expression in retinoblastoma: a marker of differentiation grade
Authors
Yue Liu
Xiufeng Zhong
Shangtao Wan
Wenxin Zhang
Jianxian Lin
Ping Zhang
Yongping Li
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Diagnostic Pathology / Issue 1/2014
Electronic ISSN: 1746-1596
DOI
https://doi.org/10.1186/s13000-014-0180-1

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