Large sporadic thyroid medullary carcinomas: predictive factors for lymph node involvement
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.
KeywordsMedullary Thyroid Carcinoma Node Desmoplasia MicroRNA
We thank B Hémon (UMR 1172, Lille) for excellent technical assistance.
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.
Compliance with ethical standards
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.
All patients having undergone a RET gene mutation analysis on a sample of lymphocyte DNA had given their written, informed consent.
- 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 25:567–610CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Sobin LH, Gospodarowicz MK, Wittekind C, International Union against C (2009) TNM classification of malignant tumours. Wiley-Blackwell, Chichester and HobokenGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle Scholar