Skip to main content

Advertisement

SpringerLink
Log in

Large sporadic thyroid medullary carcinomas: predictive factors for lymph node involvement

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Lymph node involvement (LNI) is one of the most important prognostic factors for poor survival in medullary thyroid carcinoma (MTC). At diagnosis, LNI is found in over 50% of sporadic MTCs, and especially in large tumours. Cervical lymph node dissection is therefore mandatory during MTC surgery. However, some large tumours (responsible for high preoperative basal calcitonin levels) are found to lack LNI, and can be cured definitely. Preoperative detection of these particular tumours might spare patients from undergoing extensive cervical dissection. The objective of the present retrospective study of a series of large sporadic MTCs was to identify clinical, biological and pathological factors that were predictive of LNI. Consecutive cases of large, sporadic MTCs (measuring at least 1 cm in diameter) were retrieved and reviewed. The levels of several mature microRNAs (miRs) in paraffin-embedded samples were assessed using qPCR. Of the 54 MTCs, 26 had LNI and 28 were pN0. Relative to pN0 patients, patients with LNI had a significant higher preoperative basal calcitonin level (p = 0.0074) and a greater prevalence of infiltrative margins (p < 0.0001), lymphovascular invasion (p = 0.0004), extrathyroidal extension (p < 0.0001), a higher pT stage (p = 0.0003) and more abundant desmoplastic stroma (p = 0.0006). Tumour expression levels of miR-21 (p = 0.0008) and miR-183 (p = 0.0096) were higher in the LNI group. The abundance of desmoplastic stroma (p = 0.007) and the miR-21 expression level (p = 0.0026) were independent prognostic factors for LNI. The abundance of desmoplastic stroma and high levels of miR-21 expression were strong indicators of LNI, and may thus help the surgeon to choose the extent of cervical lymph node dissection for large, sporadic MTCs with no preoperatively obvious LNI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma et al (2015) Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25:567–610

    Article  PubMed  PubMed Central  Google Scholar 

  2. Moley JF, DeBenedetti MK (1999) Patterns of nodal metastases in palpable medullary thyroid carcinoma: recommendations for extent of node dissection. Ann Surg 2:880–887 discussion 887-888

    Article  Google Scholar 

  3. Scollo C, Baudin E, Travagli J-P, Caillou B, Bellon N, Leboulleux S, Schlumberger M (2003) Rationale for central and bilateral lymph node dissection in sporadic and hereditary medullary thyroid cancer. J Clin Endocrinol Metab 88:2070–2075

    Article  CAS  PubMed  Google Scholar 

  4. Gimm O (2013) Extent of surgery in clinically evident but operable MTC—when is central and/or lateral lympadenectomy indicated? Thyroid Res 6(Suppl 1):S3

    PubMed  PubMed Central  Google Scholar 

  5. Machens A, Hauptmann S, Dralle H (2008) Prediction of lateral lymph node metastases in medullary thyroid cancer. Br J Surg 95:586–591

    Article  CAS  PubMed  Google Scholar 

  6. Machens A, Dralle H (2010) Biomarker-based risk stratification for previously untreated medullary thyroid cancer. J Clin Endocrinol Metab 95(6):2655–2663. https://doi.org/10.1210/jc.2009-2368

    Article  CAS  PubMed  Google Scholar 

  7. Garzon R, Calin GA, Croce CM (2009) MicroRNAs in cancer. Annu Rev Med 60(1):167–179. https://doi.org/10.1146/annurev.med.59.053006.104707

    Article  CAS  PubMed  Google Scholar 

  8. Pallante P, Battista S, Pierantoni GM, Fusco A (2014) Deregulation of microRNA expression in thyroid neoplasias. Nat Rev Endocrinol 10(2):88–101. https://doi.org/10.1038/nrendo.2013.223

    Article  CAS  PubMed  Google Scholar 

  9. Nikiforova MN, Tseng GC, Steward D, Diorio D, Nikiforov YE (2008) MicroRNA expression profiling of thyroid tumors: biological significance and diagnostic utility. J Clin Endocrinol Metab 93(5):1600–1608. https://doi.org/10.1210/jc.2007-2696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Abraham D, Jackson N, Gundara JS, Zhao J, Gill AJ, Delbridge L, Robinson BG, Sidhu SB (2011) MicroRNA profiling of sporadic and hereditary medullary thyroid cancer identifies predictors of nodal metastasis, prognosis, and potential therapeutic targets. Clin Cancer Res 17(14):4772–4781. https://doi.org/10.1158/1078-0432.CCR-11-0242

    Article  CAS  PubMed  Google Scholar 

  11. Mian C, Pennelli G, Fassan M, Balistreri M, Barollo S, Cavedon E, Galuppini F, Pizzi M, Vianello F, Pelizzo MR, Girelli ME, Rugge M, Opocher G (2012) MicroRNA profiles in familial and sporadic medullary thyroid carcinoma: preliminary relationships with RET status and outcome. Thyroid 22(9):890–896. https://doi.org/10.1089/thy.2012.0045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sobin LH, Gospodarowicz MK, Wittekind C, International Union against C (2009) TNM classification of malignant tumours. Wiley-Blackwell, Chichester and Hoboken

    Google Scholar 

  13. Glowacki F, Savary G, Gnemmi V, Buob D, Van der Hauwaert C, Lo-Guidice J-M, Bouyé S, Hazzan M, Pottier N, Perrais M, Aubert S, Cauffiez C (2013) Increased circulating miR-21 levels are associated with kidney fibrosis. PLoS One 8(2):e58014. https://doi.org/10.1371/journal.pone.0058014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gee HE, Buffa FM, Camps C, Ramachandran A, Leek R, Taylor M, Patil M, Sheldon H, Betts G, Homer J, West C, Ragoussis J, Harris AL (2011) The small-nucleolar RNAs commonly used for microRNA normalisation correlate with tumour pathology and prognosis. Br J Cancer 104(7):1168–1177. https://doi.org/10.1038/sj.bjc.6606076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tamagnini P, Iacobone M, Sebag F, Marcy M, De Micco C, Henry JF (2005) Lymph node involvement in macroscopic medullary thyroid carcinoma. Br J Surg 92(4):449–453. https://doi.org/10.1002/bjs.4860

    Article  CAS  PubMed  Google Scholar 

  16. Miccoli P, Minuto MN, Ugolini C, Molinaro E, Basolo F, Berti P, Pinchera A, Elisei R (2007) Clinically unpredictable prognostic factors in the outcome of medullary thyroid cancer. Endocr Relat Cancer 14(4):1099–1105. https://doi.org/10.1677/ERC-07-0128

    Article  PubMed  Google Scholar 

  17. Yip DT, Hassan M, Pazaitou-Panayiotou K, Ruan DT, Gawande AA, Gaz RD, Jr Moore FD, Hodin RA, Stephen AE, Sadow PM, Daniels GH, Randolph GW, Parangi S, Lubitz CC (2011) Preoperative basal calcitonin and tumor stage correlate with postoperative calcitonin normalization in patients undergoing initial surgical management of medullary thyroid carcinoma. Surgery 150(6):1168–1177. https://doi.org/10.1016/j.surg.2011.09.043

    Article  PubMed  Google Scholar 

  18. Koperek O, Scheuba C, Cherenko M, Neuhold N, De Micco C, Schmid KW et al (2008) Desmoplasia in medullary thyroid carcinoma: a reliable indicator of metastatic potential. Histopathology 52:6–630

    Article  Google Scholar 

  19. Kazaure HS, Roman SA, Sosa JA (2012) Medullary thyroid microcarcinoma: a population-level analysis of 310 patients. Cancer 118(3):620–627. https://doi.org/10.1002/cncr.26283

    Article  PubMed  Google Scholar 

  20. Scheuba C, Kaserer K, Kaczirek K, Asari R, Niederle B (2006) Desmoplastic stromal reaction in medullary thyroid cancer-an intraoperative “marker” for lymph node metastases. World J Surg 30:853–859

    Article  PubMed  Google Scholar 

  21. Krueger JE, Maitra A, Albores-Saavedra J (2000) Inherited medullary microcarcinoma of the thyroid: a study of 11 cases. Am J Surg Pathol 24:853–858

    Article  CAS  PubMed  Google Scholar 

  22. Machens A, Dralle H (2008) Clinical relevance of desmoplasia in medullary thyroid carcinoma. Histopathology 53:481 author reply 482-483

    Article  CAS  PubMed  Google Scholar 

  23. Wojtas B, Ferraz C, Stokowy T, Hauptmann S, Lange D, Dralle H, Musholt T, Jarzab B, Paschke R, Eszlinger M (2014) Differential miRNA expression defines migration and reduced apoptosis in follicular thyroid carcinomas. Mol Cell Endocrinol 388(1-2):1–9. https://doi.org/10.1016/j.mce.2014.02.011

    Article  CAS  PubMed  Google Scholar 

  24. Pennelli G, Galuppini F, Barollo S, Cavedon E, Bertazza L, Fassan M, Guzzardo V, Pelizzo MR, Rugge M, Mian C (2015) The PDCD4/miR-21 pathway in medullary thyroid carcinoma. Hum Pathol 46(1):50–57. https://doi.org/10.1016/j.humpath.2014.09.006

    Article  CAS  PubMed  Google Scholar 

  25. Xi Y, Nakajima G, Gavin E, Morris CG, Kudo K, Hayashi K, Ju J (2007) Systematic analysis of microRNA expression of RNA extracted from fresh frozen and formalin-fixed paraffin-embedded samples. RNA 13(10):1668–1674. https://doi.org/10.1261/rna.642907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Huang Y, Liao D, Pan L, Ye R, Li X, Wang S, Ye C, Chen L (2013) Expressions of miRNAs in papillary thyroid carcinoma and their associations with the BRAFV600E mutation. Eur J Endocrinol 168(5):675–681. https://doi.org/10.1530/EJE-12-1029

    Article  CAS  PubMed  Google Scholar 

  27. Li J, Fu H, Xu C, Tie Y, Xing R, Zhu J, Qin Y, Sun Z, Zheng X (2010) miR-183 inhibits TGF-beta1-induced apoptosis by downregulation of PDCD4 expression in human hepatocellular carcinoma cells. BMC Cancer 10(1):354. https://doi.org/10.1186/1471-2407-10-354

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zhang Z, Zha Y, Hu W, Huang Z, Gao Z, Zang Y, Chen J, Dong L, Zhang J (2013) The autoregulatory feedback loop of microRNA-21/programmed cell death protein 4/activation protein-1 (MiR-21/PDCD4/AP-1) as a driving force for hepatic fibrosis development. J Biol Chem 288(52):37082–37093. https://doi.org/10.1074/jbc.M113.517953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang Y, Gao X, Wei F, Zhang X, Yu J, Zhao H, Sun Q, Yan F, Yan C, Li H, Ren X (2014) Diagnostic and prognostic value of circulating miR-21 for cancer: a systematic review and meta-analysis. Gene 533(1):389–397. https://doi.org/10.1016/j.gene.2013.09.038

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank B Hémon (UMR 1172, Lille) for excellent technical assistance.

Author information

Author notes

  1. Amandine Berdelou and Viviane Gnemmi contributed equally to this work.

Authors and Affiliations

  1. Institut de Pathologie, Centre de Biologie Pathologie, CHRU de Lille, 59037, Lille, France

    Sébastien Aubert, Viviane Gnemmi, Florence Renaud, Brigitte Bouchindhomme & Emmanuelle Leteurtre

  2. Faculté de Médecine, Université de Lille, 59045, Lille, France

    Sébastien Aubert, Viviane Gnemmi, Robert Caiazzo, Pascal Pigny, Jean Louis Wemeau, Bruno Carnaille, Florence Renaud, Emmanuelle Leteurtre, Michael Perrais & François Pattou

  3. UMR 1172, INSERM Bâtiment Biserte, JPArc, 59045, Lille, France

    Sébastien Aubert, Viviane Gnemmi, Pascal Pigny, Florence Renaud, Emmanuelle Leteurtre & Michael Perrais

  4. Service de Cancérologie endocrinienne, IGR, 94805, Villejuif, Paris, France

    Amandine Berdelou

  5. Unité de Biostatistiques - Pôle de Santé Publique, CHRU de Lille, 59037, Lille, France

    Hélène Behal

  6. Service de Chirurgie Endocrine, Hôpital Huriez, CHRU de Lille, 59037, Lille, France

    Robert Caiazzo, Bruno Carnaille & François Pattou

  7. Institut de Biochimie, Centre de Biologie Pathologie Génétique, CHRU de Lille, 59037, Lille, France

    Michèle D’herbomez & Pascal Pigny

  8. Service d’Endocrinologie, Hôpital Huriez, CHRU de Lille, 59037, Lille, France

    Jean Louis Wemeau & Christine Do Cao

Authors
  1. Sébastien Aubert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amandine Berdelou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Viviane Gnemmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hélène Behal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert Caiazzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michèle D’herbomez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Pascal Pigny
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jean Louis Wemeau
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bruno Carnaille
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Florence Renaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Brigitte Bouchindhomme
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Emmanuelle Leteurtre
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Michael Perrais
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. François Pattou
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Christine Do Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors made substantial contributions to the conception and design of the work; acquisition, analysis and interpretation of data; and drafting and revising of the manuscript for important intellectual content. They approved the final version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Sébastien Aubert.

Ethics declarations

The present study was approved by the scientific advisory board at our institution’s biobank (Tumorothèque du C2RC, Lille, France, reference: CSTMT106).

Conflict of interest

The authors declare that they have no conflicts of interest.

Informed consent

All patients having undergone a RET gene mutation analysis on a sample of lymphocyte DNA had given their written, informed consent.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aubert, S., Berdelou, A., Gnemmi, V. et al. Large sporadic thyroid medullary carcinomas: predictive factors for lymph node involvement. Virchows Arch 472, 461–468 (2018). https://doi.org/10.1007/s00428-018-2303-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-018-2303-7

Keywords

Search

Navigation