At present, p63, TTF-1, and Napsin-A are the main immunochemical markers used to distinguish squamous cell carcinoma (SCC) from lung adenocarcinoma (ADC). However, studies using antibodies against p63 have demonstrated false-positive results with positivity in some ADC. In contrast, the expression of one of the p63 isoforms (ΔNp63), detected by the antibody p40, is highly specific for SCC. Since most cases of lung cancer are diagnosed in small specimens (cytology/biopsies) and saving material for molecular analysis is mandatory, we recommended the use of p40 (in adjunct with TTF-1 and/or Napsin-A) as the best approach to discriminate SCC and lung ADC. In this paper, we review the physiological and pathological role of p63 isoforms as well as their use as diagnostic markers in lung SCC.

Keywords:
p63, p40, Lung cancer, Squamous cell carcinoma
1.
Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dotsch V, Andrews NC, Caput D, McKeon F: p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell 1998;2:305–316.
2.
Schmale H, Bamberger C: A novel protein with strong homology to the tumor suppressor p53. Oncogene 1997;15:1363–1367.
3.
Courtois S, Verhaegh G, North S, Luciani MG, Lassus P, Hibner U, Oren M, Hainaut P: DeltaN-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53. Oncogene 2002;21:6722–6728.
4.
Westfall MD, Pietenpol JA: p63: molecular complexity in development and cancer. Carcinogenesis 2004;25:857–864.
5.
McKeon F: p63 and the epithelial stem cell: more than status quo? Genes Dev 2004;18:465–469.
6.
Lee H, Kimelman D: A dominant-negative form of p63 is required for epidermal proliferation in zebrafish. Dev Cell 2002;2:607–616.
7.
Liefer KM, Koster MI, Wang XJ, Yang A, McKeon F, Roop DR: Down-regulation of p63 is required for epidermal UV-B-induced apoptosis. Cancer Res 2000;60:4016–4020.
8.
Osada M, Ohba M, Kawahara C, Ishioka C, Kanamaru R, Katoh I, Ikawa Y, Nimura Y, Nakagawara A, Obinata M, Ikawa S: Cloning and functional analysis of human p51, which structurally and functionally resembles p53. Nat Med 1998;4:839–843.
9.
Koster MI, Kim S, Mills AA, DeMayo FJ, Roop DR: p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev 2004;18:126–131.
10.
Bakkers J, Hild M, Kramer C, Furutani-Seiki M, Hammerschmidt M: Zebrafish delta-Np63 is a direct target of bmp signaling and encodes a transcriptional repressor blocking neural specification in the ventral ectoderm. Dev Cell 2002;2:617–627.
11.
Di Como CJ, Urist MJ, Babayan I, Drobnjak M, Hedvat CV, Teruya-Feldstein J, Pohar K, Hoos A, Cordon-Cardo C: p63 expression profiles in human normal and tumor tissues. Clin Cancer Res 2002;8:494–501.
12.
Nylander K, Vojtesek B, Nenutil R, Lindgren B, Roos G, Zhanxiang W, Sjostrom B, Dahlqvist A, Coates PJ: Differential expression of p63 isoforms in normal tissues and neoplastic cells. J Pathol 2002;198:417–427.
13.
Reis-Filho JS, Milanezi F, Amendoeira I, Albergaria A, Schmitt FC: Distribution of p63, a novel myoepithelial marker, in fine-needle aspiration biopsies of the breast: an analysis of 82 samples. Cancer 2003;99:172–179.
14.
Reis-Filho JS, Milanezi F, Amendoeira I, Albergaria A, Schmitt FC: p63 staining of myoepithelial cells in breast fine needle aspirates: a study of its role in differentiating in situ from invasive ductal carcinomas of the breast. J Clin Pathol 2002;55:936–939.
15.
Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT, Tabin C, Sharpe A, Caput D, Crum C, McKeon F: p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 1999;398:714–718.
16.
Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A: p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 1999;398:708–713.
17.
Crum CP, McKeon FD: p63 in epithelial survival, germ cell surveillance, and neoplasia. Annu Rev Pathol 2010;5:349–371.
18.
Rinne T, Brunner HG, van Bokhoven H: p63-associated disorders. Cell Cycle 2007;6:262–268.
19.
Crook T, Nicholls JM, Brooks L, O’Nions J, Allday MJ: High level expression of delta- N-p63: a mechanism for the inactivation of p53 in undifferentiated nasopharyngeal carcinoma (NPC)? Oncogene 2000;19:3439–3444.
20.
Hibi K, Trink B, Patturajan M, Westra WH, Caballero OL, Hill DE, Ratovitski EA, Jen J, Sidransky D: AIS is an oncogene amplified in squamous cell carcinoma. Proc Natl Acad Sci USA 2000;97:5462–5467.
21.
Park BJ, Lee SJ, Kim JI, Lee CH, Chang SG, Park JH, Chi SG: Frequent alteration of p63 expression in human primary bladder carcinomas. Cancer Res 2000;60:3370–3374.
22.
Yamaguchi K, Wu L, Caballero OL, Hibi K, Trink B, Resto V, Cairns P, Okami K, Koch WM, Sidransky D, Jen J: Frequent gain of the p40/p51/p63 gene locus in primary head and neck squamous cell carcinoma. Int J Cancer 2000;86:684–689.
23.
Massion PP, Taflan PM, Jamshedur Rahman SM, Yildiz P, Shyr Y, Edgerton ME, Westfall MD, Roberts JR, Pietenpol JA, Carbone DP, Gonzalez AL: Significance of p63 amplification and overexpression in lung cancer development and prognosis. Cancer Res 2003;63:7113–7121.
24.
Buckley NE, Conlon SJ, Jirstrom K, Kay EW, Crawford NT, O’Grady A, Sheehan K, Mc Dade SS, Wang CW, McCance DJ, Johnston PG, Kennedy RD, Harkin DP, Mullan PB: The DeltaNp63 proteins are key allies of brca1 in the prevention of basal-like breast cancer. Cancer Res 2011;71:1933–1944.
25.
Adorno M, Cordenonsi M, Montagner M, Dupont S, Wong C, Hann B, Solari A, Bobisse S, Rondina MB, Guzzardo V, Parenti AR, Rosato A, Bicciato S, Balmain A, Piccolo S: A mutant-p53/smad complex opposes p63 to empower tgfbeta-induced metastasis. Cell 2009;137:87–98.
26.
Carroll DK, Carroll JS, Leong CO, Cheng F, Brown M, Mills AA, Brugge JS, Ellisen LW: p63 regulates an adhesion programme and cell survival in epithelial cells. Nat Cell Biol 2006;8:551–561.
27.
Hu M, Yao J, Carroll DK, Weremowicz S, Chen H, Carrasco D, Richardson A, Violette S, Nikolskaya T, Nikolsky Y, Bauerlein EL, Hahn WC, Gelman RS, Allred C, Bissell MJ, Schnitt S, Polyak K: Regulation of in situ to invasive breast carcinoma transition. Cancer Cell 2008;13:394–406.
28.
Hagiwara K, McMenamin MG, Miura K, Harris CC: Mutational analysis of the p63/p73L/p51/p40/CUSP/KET gene in human cancer cell lines using intronic primers. Cancer Res 1999;59:4165–4169.
29.
Takeuchi Y, Tamura A, Kamiya M, Fukuda T, Ishikawa O: Immunohistochemical analyses of p63 expression in cutaneous tumours. Br J Dermatol 2005;153:1230–1232.
30.
Quade BJ, Yang A, Wang Y, Sun D, Park J, Sheets EE, Cviko A, Federschneider JM, Peters R, McKeon FD, Crum CP: Expression of the p53 homologue p63 in early cervical neoplasia. Gynecol Oncol 2001;80:24–29.
31.
Lin Z, Liu M, Li Z, Kim C, Lee E, Kim I: DeltaNp63 protein expression in uterine cervical and endometrial cancers. J Cancer Res Clin Oncol 2006;132:811–816.
32.
Senoo M, Tsuchiya I, Matsumura Y, Mori T, Saito Y, Kato H, Okamoto T, Habu S: Transcriptional dysregulation of the p73L/p63/p51/p40/KET gene in human squamous cell carcinomas: expression of Delta Np73L, a novel dominant-negative isoform, and loss of expression of the potential tumour suppressor p51. Br J Cancer 2001;84:1235–1241.
33.
Bockmuhl U, Schwendel A, Dietel M, Petersen I: Distinct patterns of chromosomal alterations in high- and low-grade head and neck squamous cell carcinomas. Cancer Res 1996;56:5325–5329.
34.
Bjorkqvist AM, Husgafvel-Pursiainen K, Anttila S, Karjalainen A, Tammilehto L, Mattson K, Vainio H, Knuutila S: DNA gains in 3q occur frequently in squamous cell carcinoma of the lung, but not in adenocarcinoma. Genes Chromosomes Cancer 1998;22:79–82.
35.
Choi HR, Batsakis JG, Zhan F, Sturgis E, Luna MA, El-Naggar AK: Differential expression of p53 gene family members p63 and p73 in head and neck squamous tumorigenesis. Hum Pathol 2002;33:158–164.
36.
Hu H, Xia SH, Li AD, Xu X, Cai Y, Han YL, Wei F, Chen BS, Huang XP, Han YS, Zhang JW, Zhang X, Wu M, Wang MR: Elevated expression of p63 protein in human esophageal squamous cell carcinomas. Int J Cancer 2002;102:580–583.
37.
Dellavalle RP, Walsh P, Marchbank A, Grayson TE, Su LJ, Parker ER, DeGregori J, Penheiter K, Aszterbaum M, Epstein EH Jr, Lee LA: Cusp/p63 expression in basal cell carcinoma. Exp Dermatol 2002;11:203–208.
38.
Davis LD, Zhang W, Merseburger A, Young D, Xu L, Rhim JS, Moul JW, Srivastava S, Sesterhenn IA: p63 expression profile in normal and malignant prostate epithelial cells. Anticancer Res 2002;22:3819–3825.
39.
Garraway LA, Lin D, Signoretti S, Waltregny D, Dilks J, Bhattacharya N, Loda M: Intermediate basal cells of the prostate: in vitro and in vivo characterization. Prostate 2003;55:206–218.
40.
Weinstein MH, Signoretti S, Loda M: Diagnostic utility of immunohistochemical staining for p63, a sensitive marker of prostatic basal cells. Mod Pathol 2002;15:1302–1308.
41.
Massion PP, Kuo WL, Stokoe D, Olshen AB, Treseler PA, Chin K, Chen C, Polikoff D, Jain AN, Pinkel D, Albertson DG, Jablons DM, Gray JW: Genomic copy number analysis of non-small cell lung cancer using array comparative genomic hybridization: implications of the phosphatidylinositol 3-kinase pathway. Cancer Res 2002;62:3636–3640.
42.
Pelosi G, Pasini F, Olsen Stenholm C, Pastorino U, Maisonneuve P, Sonzogni A, Maffini F, Pruneri G, Fraggetta F, Cavallon A, Roz E, Iannucci A, Bresaola E, Viale G: p63 immunoreactivity in lung cancer: yet another player in the development of squamous cell carcinomas? J Pathol 2002;198:100–109.
43.
Wang BY, Gil J, Kaufman D, Gan L, Kohtz DS, Burstein DE: p63 in pulmonary epithelium, pulmonary squamous neoplasms, and other pulmonary tumors. Hum Pathol 2002;33:921–926.
44.
Sniezek JC, Matheny KE, Burkey BB, Netterville JL, Pietenpol JA: Expression of p63 and 14-3-3sigma in normal and hyperdifferentiated mucosa of the upper aerodigestive tract. Otolaryngol Head Neck Surg 2002;126:598–601.
45.
Nonaka D: A study of deltaNp63 expression in lung non-small cell carcinomas. Am J Surg Pathol 2012;36:895–899.
46.
Pelosi G, Fabbri A, Bianchi F, Maisonneuve P, Rossi G, Barbareschi M, Graziano P, Cavazza A, Rekhtman N, Pastorino U, Scanagatta P, Papotti M: DeltaNp63 (p40) and thyroid transcription factor-1 immunoreactivity on small biopsies or cellblocks for typing non-small cell lung cancer: a novel two-hit, sparing-material approach. J Thorac Oncol 2012;7:281–290.
47.
Bishop JA, Teruya-Feldstein J, Westra WH, Pelosi G, Travis WD, Rekhtman N: P40 (deltaNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma. Mod Pathol 2012;25:405–415.
48.
Uramoto H, Yamada S, Hanagiri T: Immunohistochemical staining with deltaNp63 is useful for distinguishing the squamous cell component of adenosquamous cell carcinoma of the lung. Anticancer Res 2010;30:4717–4720.
49.
Righi L, Graziano P, Fornari A, Rossi G, Barbareschi M, Cavazza A, Pelosi G, Scagliotti GV, Papotti M: Immunohistochemical subtyping of nonsmall cell lung cancer not otherwise specified in fine-needle aspiration cytology: a retrospective study of 103 cases with surgical correlation. Cancer 2011;117:3416–3423.
50.
Yoshizawa A, Motoi N, Riely GJ, Sima CS, Gerald WL, Kris MG, Park BJ, Rusch VW, Travis WD: Impact of proposed iaslc/ats/ers classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol 2011;24:653–664.
51.
Sica G, Yoshizawa A, Sima CS, Azzoli CG, Downey RJ, Rusch VW, Travis WD, Moreira AL: A grading system of lung adenocarcinomas based on histologic pattern is predictive of disease recurrence in stage I tumors. Am J Surg Pathol 2010;34:1155–1162.
© 2012 S. Karger AG, Basel
2012
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.