Virchows Archiv

, Volume 462, Issue 6, pp 619–632 | Cite as

Retinoid acid receptor expression is helpful to distinguish between adenoma and well-differentiated carcinoma in the thyroid

  • Guillaume GauchotteEmail author
  • Stéphanie Lacomme
  • Lydia Brochin
  • Benjamin Tournier
  • Virginie Cahn
  • Nathalie Monhoven
  • Françoise Piard
  • Marc Klein
  • Nadine Martinet
  • Cécile Rochette-Egly
  • Jean-Michel Vignaud
Original Article


Retinoid receptors (RRs) play a key role in cell proliferation and differentiation. We characterized the expression of RA receptors and retinoid X receptors (RARs and RXRs) in a series of 111 thyroid tumors and investigated the mechanisms responsible for their deregulation: hypermethylation of the RARB2 promoter, loss of heterozygosity (LOH) in the regions of RARB and RXRA, and altered expression of CRBP1 and enzymes involved in RA biosynthesis (RDH10 and RALDH2). Expression of RALDH2 and RDH10 was conserved in 100 % of adenomas and in 90 and 98 %, respectively, of carcinomas, whereas staining for CRBP1 was decreased in 9 % of FAs and 28 % of carcinomas, mainly anaplastic carcinomas (55 %). We found an abnormal expression of RARA, RARB, RXRA, and RXRB in 67, 69, 66, and 73 %, respectively, of thyroid carcinomas (n = 78) and in 9, 9, 9, and 33 % of follicular adenomas (n = 33) (p < 0.001). An abnormal staining pattern of at least two of these markers had 90 % sensitivity and 91 % specificity for a diagnosis of malignancy. Promoter hypermethylation of RARB2 was observed in some anaplastic carcinomas (14 %). LOH was found to be common at the RARB locus (3p24–3p25) and the RXRA locus (9q34), respectively, in 44 and 55 % of carcinomas and in 27 and 43 % of adenomas. In conclusion, immunohistochemical staining for RARs and RXRs may help in the differential diagnosis between well-differentiated carcinoma and follicular adenoma. Further investigation should be carried out to determine whether the characterization of RR expression might identify patients who could benefit from therapy with RA derivatives.


Retinoids RAR RXR Promoter methylation Loss of heterozygosity Thyroid cancer 



The authors thank Mrs. Caroline Chapusot (Department of Pathology, CHU Dijon), Mrs. Brigitte Léotard, Ms. Aline Saunier (Department of Genetics, CHU Nancy), Ms. Julie Zinszner (Department of Pathology, CHU Nancy) for technical support, Mr. Marc Soudant (Epidemiology and Clinical Evaluation, CHU Nancy) for statistical analysis, and Mrs. Jacqueline Zevnick for reviewing the manuscript.

Conflict of interest

The authors have no conflict of interest to declare.


  1. 1.
    Kastner P, Mark M, Chambon P (1995) Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 83:859–869PubMedCrossRefGoogle Scholar
  2. 2.
    Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM (1995) The nuclear receptor superfamily: the second decade. Cell 83:835–839PubMedCrossRefGoogle Scholar
  3. 3.
    Coelho SM, Vaisman M, Carvalho DP (2005) Tumour re-differentiation effect of retinoic acid: a novel therapeutic approach for advanced thyroid cancer. Curr Pharm Des 11:2525–2531PubMedCrossRefGoogle Scholar
  4. 4.
    Fernandez CA, Puig-Domingo M, Lomena F, Estorch M, Camacho Marti V, Bittini AL, Marazuela M, Santamaria J, Castro J, Martinez de Icaya P, Moraga I, Martin T, Megia A, Porta M, Mauricio D, Halperin I (2009) Effectiveness of retinoic acid treatment for redifferentiation of thyroid cancer in relation to recovery of radioiodine uptake. J Endocrinol Invest 32:228–233. Google Scholar
  5. 5.
    Zhang Y, Jia S, Liu Y, Li B, Wang Z, Lu H, Zhu C (2007) A clinical study of all-trans-retinoid-induced differentiation therapy of advanced thyroid cancer. Nucl Med Commun 28:251–255PubMedCrossRefGoogle Scholar
  6. 6.
    Simon D, Korber C, Krausch M, Segering J, Groth P, Gorges R, Grunwald F, Muller-Gartner HW, Schmutzler C, Kohrle J, Roher HD, Reiners C (2002) Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: final results of a pilot study. Eur J Nucl Med Mol Imaging 29:775–782. doi: 10.1007/s00259-001-0737-6 PubMedCrossRefGoogle Scholar
  7. 7.
    Zhang XK, Liu Y, Lee MO, Pfahl M (1994) A specific defect in the retinoic acid response associated with human lung cancer cell lines. Cancer Res 54:5663–5669PubMedGoogle Scholar
  8. 8.
    Schmutzler C, Hoang-Vu C, Ruger B, Kohrle J (2004) Human thyroid carcinoma cell lines show different retinoic acid receptor repertoires and retinoid responses. Eur J Endocrinol 150:547–556PubMedCrossRefGoogle Scholar
  9. 9.
    Haugen BR, Larson LL, Pugazhenthi U, Hays WR, Klopper JP, Kramer CA, Sharma V (2004) Retinoic acid and retinoid X receptors are differentially expressed in thyroid cancer and thyroid carcinoma cell lines and predict response to treatment with retinoids. J Clin Endocrinol Metab 89:272–280PubMedCrossRefGoogle Scholar
  10. 10.
    Cras A, Darsin-Bettinger D, Balitrand N, Cassinat B, Soulie A, Toubert ME, Delva L, Chomienne C (2007) Epigenetic patterns of the retinoic acid receptor beta2 promoter in retinoic acid-resistant thyroid cancer cells. Oncogene 26:4018–4024. doi: 10.1038/sj.onc.1210178 PubMedCrossRefGoogle Scholar
  11. 11.
    Elisei R, Vivaldi A, Agate L, Ciampi R, Molinaro E, Piampiani P, Romei C, Faviana P, Basolo F, Miccoli P, Capodanno A, Collecchi P, Pacini F, Pinchera A (2005) All-trans-retinoic acid treatment inhibits the growth of retinoic acid receptor beta messenger ribonucleic acid expressing thyroid cancer cell lines but does not reinduce the expression of thyroid-specific genes. J Clin Endocrinol Metab 90:2403–2411PubMedCrossRefGoogle Scholar
  12. 12.
    Martinet N, Alla F, Farre G, Labib T, Drouot H, Vidili R, Picard E, Gaube MP, Le Faou D, Siat J, Borelly J, Vermylen P, Bazarbachi T, Vignaud JM, Martinet Y (2000) Retinoic acid receptor and retinoid X receptor alterations in lung cancer precursor lesions. Cancer Res 60:2869–2875PubMedGoogle Scholar
  13. 13.
    Bovenzi V, Le NL, Cote S, Sinnett D, Momparler LF, Momparler RL (1999) DNA methylation of retinoic acid receptor beta in breast cancer and possible therapeutic role of 5-aza-2′-deoxycytidine. Anticancer Drugs 10:471–476PubMedCrossRefGoogle Scholar
  14. 14.
    Hoque MO, Rosenbaum E, Westra WH, Xing M, Ladenson P, Zeiger MA, Sidransky D, Umbricht CB (2005) Quantitative assessment of promoter methylation profiles in thyroid neoplasms. J Clin Endocrinol Metab 90:4011–4018. doi: 10.1210/jc.2005-0313 PubMedCrossRefGoogle Scholar
  15. 15.
    Gauchotte G, Philippe C, Lacomme S, Leotard B, Wissler MP, Allou L, Toussaint B, Klein M, Vignaud JM, Bressenot A (2011) BRAF, p53 and SOX2 in anaplastic thyroid carcinoma: evidence for multistep carcinogenesis. Pathology 43:447–452. doi: 10.1097/PAT.0b013e3283486178 PubMedCrossRefGoogle Scholar
  16. 16.
    Hoftijzer HC, Liu YY, Morreau H, van Wezel T, Pereira AM, Corssmit EP, Romijn JA, Smit JW (2009) Retinoic acid receptor and retinoid X receptor subtype expression for the differential diagnosis of thyroid neoplasms. Eur J Endocrinol 160:631–638. doi: 10.1530/EJE-08-0812 PubMedCrossRefGoogle Scholar
  17. 17.
    Rochaix P, Monteil-Onteniente S, Rochette-Egly C, Caratero C, Voigt JJ, Jozan S (1998) Reduced expression of retinoic acid receptor beta protein (RAR beta) in human papillary thyroid carcinoma: immunohistochemical and western blot study. Histopathology 33:337–343PubMedCrossRefGoogle Scholar
  18. 18.
    Takiyama Y, Miyokawa N, Sugawara A, Kato S, Ito K, Sato K, Oikawa K, Kobayashi H, Kimura S, Tateno M (2004) Decreased expression of retinoid X receptor isoforms in human thyroid carcinomas. J Clin Endocrinol Metab 89:5851–5861. doi: 10.1210/jc.2003-032036 PubMedCrossRefGoogle Scholar
  19. 19.
    Grunwald F, Pakos E, Bender H, Menzel C, Otte R, Palmedo H, Pfeifer U, Biersack HJ (1998) Redifferentiation therapy with retinoic acid in follicular thyroid cancer. J Nucl Med 39:1555–1558PubMedGoogle Scholar
  20. 20.
    Hoffmann S, Rockenstein A, Ramaswamy A, Celik I, Wunderlich A, Lingelbach S, Hofbauer LC, Zielke A (2007) Retinoic acid inhibits angiogenesis and tumor growth of thyroid cancer cells. Mol Cell Endocrinol 264:74–81PubMedCrossRefGoogle Scholar
  21. 21.
    Lee ES, Issa JP, Roberts DB, Williams MD, Weber RS, Kies MS, El-Naggar AK (2008) Quantitative promoter hypermethylation analysis of cancer-related genes in salivary gland carcinomas: comparison with methylation-specific PCR technique and clinical significance. Clin Cancer Res 14:2664–2672. doi: 10.1158/1078-0432.CCR-07-1232 PubMedCrossRefGoogle Scholar
  22. 22.
    Li R, Saito T, Tanaka R, Satohisa S, Adachi K, Horie M, Akashi Y, Kudo R (2005) Hypermethylation in promoter region of retinoic acid receptor-beta gene and immunohistochemical findings on retinoic acid receptors in carcinogenesis of endometrium. Cancer Lett 219:33–40. doi: 10.1016/j.canlet.2004.06.044 PubMedCrossRefGoogle Scholar
  23. 23.
    Hu S, Liu D, Tufano RP, Carson KA, Rosenbaum E, Cohen Y, Holt EH, Kiseljak-Vassiliades K, Rhoden KJ, Tolaney S, Condouris S, Tallini G, Westra WH, Umbricht CB, Zeiger MA, Califano JA, Vasko V, Xing M (2006) Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. Int J Cancer 119:2322–2329PubMedCrossRefGoogle Scholar
  24. 24.
    Mohammadi-Asl J, Larijani B, Khorgami Z, Tavangar SM, Haghpanah V, Kheirollahi M, Mehdipour P (2011) Qualitative and quantitative promoter hypermethylation patterns of the P16, TSHR, RASSF1A and RARbeta2 genes in papillary thyroid carcinoma. Med Oncol 28:1123–1128. doi: 10.1007/s12032-010-9587-z PubMedCrossRefGoogle Scholar
  25. 25.
    Schagdarsurengin U, Gimm O, Dralle H, Hoang-Vu C, Dammann R (2006) CpG island methylation of tumor-related promoters occurs preferentially in undifferentiated carcinoma. Thyroid 16:633–642. doi: 10.1089/thy.2006.16.633 PubMedCrossRefGoogle Scholar
  26. 26.
    Ward LS, Brenta G, Medvedovic M, Fagin JA (1998) Studies of allelic loss in thyroid tumors reveal major differences in chromosomal instability between papillary and follicular carcinomas. J Clin Endocrinol Metab 83:525–530PubMedCrossRefGoogle Scholar
  27. 27.
    Miller WH Jr (1998) The emerging role of retinoids and retinoic acid metabolism blocking agents in the treatment of cancer. Cancer 83:1471–1482. doi: 10.1002/(SICI)1097-0142(19981015)83:8<1471::AID-CNCR1>3.0.CO;2–6 PubMedCrossRefGoogle Scholar
  28. 28.
    Ruggeri RM, Campenni A, Baldari S, Trimarchi F, Trovato M (2008) What is new on thyroid cancer biomarkers. Biomark Insights 3:237–252PubMedGoogle Scholar
  29. 29.
    Sigstad E, Paus E, Bjoro T, Berner A, Groholt KK, Jorgensen LH, Sobrinho-Simoes M, Holm R, Warren DJ (2012) The new molecular markers DDIT3, STT3A, ARG2 and FAM129A are not useful in diagnosing thyroid follicular tumors. Mod Pathol 25:537–547. doi: 10.1038/modpathol.2011.188 PubMedCrossRefGoogle Scholar
  30. 30.
    Zhu L, Santos NC, Kim KH (2009) Small ubiquitin-like modifier-2 modification of retinoic acid receptor-alpha regulates its subcellular localization and transcriptional activity. Endocrinology 150:5586–5595. doi: 10.1210/en.2009-0868 PubMedCrossRefGoogle Scholar
  31. 31.
    Zhou H, Liu W, Su Y, Wei Z, Liu J, Kolluri SK, Wu H, Cao Y, Chen J, Wu Y, Yan T, Cao X, Gao W, Molotkov A, Jiang F, Li WG, Lin B, Zhang HP, Yu J, Luo SP, Zeng JZ, Duester G, Huang PQ, Zhang XK (2010) NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling. Cancer Cell 17:560–573. doi: 10.1016/j.ccr.2010.04.023 PubMedCrossRefGoogle Scholar
  32. 32.
    Shaw RJ, Akufo-Tetteh EK, Risk JM, Field JK, Liloglou T (2006) Methylation enrichment pyrosequencing: combining the specificity of MSP with validation by pyrosequencing. Nucleic Acids Res 34:e78. doi: 10.1093/nar/gkl424 PubMedCrossRefGoogle Scholar
  33. 33.
    Choi CH, Lee KM, Choi JJ, Kim TJ, Kim WY, Lee JW, Lee SJ, Lee JH, Bae DS, Kim BG (2007) Hypermethylation and loss of heterozygosity of tumor suppressor genes on chromosome 3p in cervical cancer. Cancer Lett 255:26–33. doi: 10.1016/j.canlet.2007.03.015 PubMedCrossRefGoogle Scholar
  34. 34.
    Yang Q, Yoshimura G, Nakamura M, Nakamura Y, Shan L, Suzuma T, Tamaki T, Umemura T, Mori I, Kakudo K (2001) Allelic loss of chromosome 3p24 correlates with tumor progression rather than with retinoic acid receptor beta2 expression in breast carcinoma. Breast Cancer Res Treat 70:39–45PubMedCrossRefGoogle Scholar
  35. 35.
    Napoli JL (2012) Physiological insights into all-trans-retinoic acid biosynthesis. Biochim Biophys Acta 1821:152–167. doi: 10.1016/j.bbalip.2011.05.004 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Guillaume Gauchotte
    • 1
    • 3
    • 8
    Email author
  • Stéphanie Lacomme
    • 2
  • Lydia Brochin
    • 1
  • Benjamin Tournier
    • 4
  • Virginie Cahn
    • 1
  • Nathalie Monhoven
    • 1
  • Françoise Piard
    • 4
  • Marc Klein
    • 5
  • Nadine Martinet
    • 6
  • Cécile Rochette-Egly
    • 7
  • Jean-Michel Vignaud
    • 1
    • 2
    • 3
  1. 1.Department of PathologyCHUNancyFrance
  2. 2.Centre de Ressources BiologiquesCHUNancyFrance
  3. 3.Medical FacultyINSERM U954NancyFrance
  4. 4.Department of Pathology and Molecular OncologyCHUDijonFrance
  5. 5.Department of Endocrinology, Hôpitaux de BraboisCHUVandoeuvre-lès-NancyFrance
  6. 6.Institut de Chimie de Nice, UMR 7272University of Nice Sophia-AntipolisNiceFrance
  7. 7.Génomique fonctionnelle et cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U964; CNRS, UMR 7104University of StrasbourgIllkirchFrance
  8. 8.Service d’Anatomie et Cytologie Pathologiques, Hôpital CentralCHU de NancyNancyFrance

Personalised recommendations