Skip to main content
Log in

Should subcentimeter non-invasive encapsulated, follicular variant of papillary thyroid carcinoma be included in the noninvasive follicular thyroid neoplasm with papillary-like nuclear features category?

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Objective

In 2016, non-invasive, well-circumscribed and encapsulated, follicular variant of papillary thyroid carcinoma (NI-EFV PTC) was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in order to reduce overtreatment of this indolent tumor. However, the study cohort did not include subcentimeter tumors, i.e., papillary thyroid microcarcinoma (mPTC) with NI-EFV morphology, and such lesions are still regarded and staged by most pathologists as microcarcinomas. It is therefore crucial to evaluate the clinical outcome of subcentimeter NI-EFVs.

Methods

A total of 52 patients with unifocal mPTC, NI-EFV from five tertiary hospitals who had at least one year clinical follow-up (FU) without post-operative RAI administration were included in the study. A control group of 57 invasive mPTC follicular variant was also included.

Results

The median tumor size was 0.44 cm (range 0.1–0.9 cm). There were no distant or lymph node metastases at diagnosis in all patients. Twenty-three patients (44%) underwent lobectomy alone, while the remaining received total thyroidectomy. No recurrence was observed in the entire cohort (n = 52) including all 38 patients with at least 2 years of FU (median FU: 6.3 years). Among 25 patients with ≥5 years of FU, none recurred with a median FU of 9.6 years (range 5.2–18.1 years). In contrast, in the control group with invasive mPTC follicular variant, there were 5 (9%) patients with nodal metastasis at presentation and 1 (2%) who displayed nodal recurrence.

Conclusion

Papillary thyroid microcarcinoma, NI-EFV, when stringently selected for, lacks metastasis at presentation and follows an extremely indolent clinical course, even when treated conservatively without RAI therapy. Provided stringent inclusion criteria are met, classification of subcentimeter mPTC, NI-EFV as NIFTP should be considered in order to avoid overtreatment of these biologically indolent lesions.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. H. Lim, S.S. Devesa, J.A. Sosa, D. Check, C.M. Kitahara, Trends in thyroid cancer incidence and mortality in the United States, 1974–2013. JAMA 317(13), 1338–1348 (2017). https://doi.org/10.1001/jama.2017.2719

    Article  PubMed  Google Scholar 

  2. R. Siegel, J. Ma, Z. Zou, A. Jemal, Cancer statistics, 2014. Cancer J. Clin. 64(1), 9–29 (2014). https://doi.org/10.3322/caac.21208

    Article  Google Scholar 

  3. C.K. Jung, M.P. Little, J.H. Lubin, A.V. Brenner, S.A. Wells Jr., A.J. Sigurdson et al., The increase in thyroid cancer incidence during the last four decades is accompanied by a high frequency of BRAF mutations and a sharp increase in RAS mutations. J. Clin. Endocrinol. Metab. 99(2), E276–E285 (2014). https://doi.org/10.1210/jc.2013-2503

    Article  CAS  PubMed  Google Scholar 

  4. Y.E. Nikiforov, R.R. Seethala, G. Tallini, Z.W. Baloch, F. Basolo, L.D. Thompson et al., Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2, 1023–1029 (2016). https://doi.org/10.1001/jamaoncol.2016.0386

    Article  PubMed  PubMed Central  Google Scholar 

  5. R.A. DeLellis, R.V. Lloyd, P.U. Heitz, C. Eng. Pathology and genetics of tumours of the endocrine organs, 3rd edn. (IARC Press, Lyon, 2004)

    Google Scholar 

  6. Cancer Genome Atlas Research Network, Integrated genomic characterization of papillary thyroid carcinoma. Cell 159(3), 676–690 (2014). https://doi.org/10.1016/j.cell.2014.09.050

    Article  Google Scholar 

  7. M. Rivera, J. Ricarte-Filho, J. Knauf, A. Shaha, M. Tuttle, J.A. Fagin et al., Molecular genotyping of papillary thyroid carcinoma follicular variant according to its histological subtypes (encapsulated vs infiltrative) reveals distinct BRAF and RAS mutation patterns. Mod. Pathol. 23(9), 1191–1200 (2010). https://doi.org/10.1038/modpathol.2010.112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. J. Liu, B. Singh, G. Tallini, D.L. Carlson, N. Katabi, A. Shaha et al., Follicular variant of papillary thyroid carcinoma: a clinicopathologic study of a problematic entity. Cancer 107(6), 1255–1264 (2006). https://doi.org/10.1002/cncr.22138

    Article  PubMed  Google Scholar 

  9. Z. Zhu, M. Gandhi, M.N. Nikiforova, A.H. Fischer, Y.E. Nikiforov, Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations. Am. J. Clin. Pathol. 120(1), 71–77 (2003). https://doi.org/10.1309/ND8D-9LAJ-TRCT-G6QD

    Article  CAS  PubMed  Google Scholar 

  10. P.W. Rosario, G.C. Penna, M.R. Calsolari, Noninvasive encapsulated follicular variant of papillary thyroid carcinoma: is lobectomy sufficient for tumours >/=1 cm? Clin. Endocrinol. 81(4), 630–632 (2014). https://doi.org/10.1111/cen.12387

    Article  Google Scholar 

  11. F. Cecoli, E.M. Ceresola, V. Altrinetti, M. Cabria, M. Cappagli, A. Montepagani et al., Therapeutic strategies and clinical outcome in papillary thyroid microcarcinoma: a multicenter observational study. Eur. Thyroid J. 5(3), 180–186 (2016). https://doi.org/10.1159/000446746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. B.R.M. Haugen, E.K. Alexander, K.C. Bible, G. Doherty, S.J. Mandel, Y.E. Nikiforov et al., 2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid 26, 1–133 (2016). https://doi.org/10.1089/thy.2015.0020

    Article  PubMed  PubMed Central  Google Scholar 

  13. R.I. Haddad, W.M. Lydiatt, L. Bischoff, N.L. Busaidy, D.R. Byrd, G. Callender et al., NCCN Clinical Practice Guidelines in Oncology (NCCN guidelines): Thyroid Carcinoma Version 1. (National Comprehensive Cancer Network, 2017). https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf

  14. C.A. Routhier, M.C. Mochel, K. Lynch, D. Dias-Santagata, D.N. Louis, M.P. Hoang, Comparison of 2 monoclonal antibodies for immunohistochemical detection of BRAF V600E mutation in malignant melanoma, pulmonary carcinoma, gastrointestinal carcinoma, thyroid carcinoma, and gliomas. Hum. Pathol. 44(11), 2563–2570 (2013). https://doi.org/10.1016/j.humpath.2013.06.018

    Article  CAS  PubMed  Google Scholar 

  15. G. Tallini, R.M. Tuttle, R.A. Ghossein. The history of the follicular variant of papillary thyroid carcinoma. J. Clin. Endocrinol. Metabol. jc20162976 (2016). https://doi.org/10.1210/jc.2016-2976

  16. S. Vaccarella, S. Franceschi, F. Bray, C.P. Wild, M. Plummer, L. Dal Maso, Worldwide thyroid-cancer epidemic? The increasing impact of overdiagnosis. N. Engl. J. Med. 375(7), 614–617 (2016). https://doi.org/10.1056/NEJMp1604412

    Article  PubMed  Google Scholar 

  17. J. Rosai, V.A. LiVolsi, M. Sobrinho-Simoes, E.D. Williams, Renaming papillary microcarcinoma of the thyroid gland: the Porto proposal. Int. J. Surg. Pathol. 11(4), 249–251 (2003). https://doi.org/10.1177/106689690301100401

    Article  PubMed  Google Scholar 

  18. R. Ghossein, I. Ganly, A. Biagini, E. Robenshtok, M. Rivera, R.M. Tuttle, Prognostic factors in papillary microcarcinoma with emphasis on histologic subtyping: a clinicopathologic study of 148 cases. Thyroid 24(2), 245–253 (2014). https://doi.org/10.1089/thy.2012.0645

    Article  CAS  PubMed  Google Scholar 

  19. S. Piana, M. Ragazzi, G. Tallini, D. de Biase, A. Ciarrocchi, A. Frasoldati et al., Papillary thyroid microcarcinoma with fatal outcome: evidence of tumor progression in lymph node metastases: report of 3 cases, with morphological and molecular analysis. Hum. Pathol. 44(4), 556–565 (2013). https://doi.org/10.1016/j.humpath.2012.06.019

    Article  PubMed  Google Scholar 

  20. L.D. Thompson, Ninety-four cases of encapsulated follicular variant of papillary thyroid carcinoma: a name change to noninvasive follicular thyroid neoplasm with papillary-like nuclear features would help prevent overtreatment. Mod. Pathol. 29(7), 698–707 (2016). https://doi.org/10.1038/modpathol.2016.65

    Article  CAS  PubMed  Google Scholar 

  21. M. Rivera, R.M. Tuttle, S. Patel, A. Shaha, J.P. Shah, R.A. Ghossein, Encapsulated papillary thyroid carcinoma: a clinico-pathologic study of 106 cases with emphasis on its morphologic subtypes (histologic growth pattern). Thyroid 19(2), 119–127 (2009). https://doi.org/10.1089/thy.2008.0303

    Article  PubMed  Google Scholar 

  22. B.E. Howitt, V.A. Paulson, J.A. Barletta, Absence of BRAF V600E in non-infiltrative, non-invasive follicular variant of papillary thyroid carcinoma. Histopathology 67(4), 579–582 (2015). https://doi.org/10.1111/his.12680

    Article  PubMed  Google Scholar 

  23. U. Cho, O. Mete, M.H. Kim, J.S. Bae, C.K. Jung, Molecular correlates and rate of lymph node metastasis of non-invasive follicular thyroid neoplasm with papillary-like nuclear features and invasive follicular variant papillary thyroid carcinoma: the impact of rigid criteria to distinguish non-invasive follicular thyroid neoplasm with papillary-like nuclear features. Mod. Pathol. 30, 810–825 (2017). https://doi.org/10.1038/modpathol.2017.9

    Article  CAS  PubMed  Google Scholar 

  24. L. Zhao, D. Dias-Santagata, P.M. Sadow, W.C. Faquin, Cytological, molecular, and clinical features of noninvasive follicular thyroid neoplasm with papillary-like nuclear features versus invasive forms of follicular variant of papillary thyroid carcinoma. Cancer 125, 323–331 (2017). https://doi.org/10.1002/cncy.21839

    CAS  Google Scholar 

  25. Y.E. Nikiforov, R.R. Seethala, G. Tallini, Z.W. Baloch, F. Basolo, L.D. Thompson et al., Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2(8), 1023–1029 (2016). https://doi.org/10.1001/jamaoncol.2016.0386

    Article  PubMed  PubMed Central  Google Scholar 

  26. E.L. Mazzaferri, S.M. Jhiang, Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am. J. Med. 97(5), 418–428 (1994)

    Article  CAS  PubMed  Google Scholar 

  27. J.F. Nwatsock, D. Taieb, F.D. Zok, O. Mundler, Late recurrences of thyroid carcinoma 24 years after a complete remission: When monitoring should be stopped? World J. Nucl. Med. 11(1), 42–43 (2012). https://doi.org/10.4103/1450-1147.98749

    Article  PubMed  PubMed Central  Google Scholar 

  28. I. Ganly, L. Wang, R.M. Tuttle, N. Katabi, G.A. Ceballos, H.R. Harach et al., Invasion rather than nuclear features correlates with outcome in encapsulated follicular tumors: further evidence for the reclassification of the encapsulated papillary thyroid carcinoma follicular variant. Hum. Pathol. 46(5), 657–664 (2015). https://doi.org/10.1016/j.humpath.2015.01.010

    Article  PubMed  PubMed Central  Google Scholar 

  29. B. Xu, G. Tallini, T. Scognamiglio, B.R. Roman, R.M. Tuttle, R.A. Ghossein, Outcome of large noninvasive follicularthyroid neoplasm with papillary-like nuclear features. Thyroid 27(4), 512–517 (2017). https://doi.org/10.1089/thy.2016.0649

    Article  CAS  PubMed  Google Scholar 

  30. J. Rosai, R.A. DeLellis, M.L. Carcangiu, W.J. Frable, T. G. Tumor of the Thyroid and Parathyroid Gland (AFIP Atlas of Tumor Pathology Series 4). (American Registry of Pathology Press, Silver Spring, MD, 2015)

    Google Scholar 

  31. C. La Vecchia, M. Malvezzi, C. Bosetti, W. Garavello, P. Bertuccio, F. Levi et al., Thyroid cancer mortality and incidence: a global overview. Int. J. Cancer 136(9), 2187–2195 (2015). https://doi.org/10.1002/ijc.29251

    Article  PubMed  Google Scholar 

  32. J. Rosai, Papillary thyroid carcinoma: a root-and-branch rethink. Am. J. Clin. Pathol. 130(5), 683–686 (2008). https://doi.org/10.1309/AJCPBF63BWMCYSLW

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Research reported in this publication was supported in part by an Italian Government-Ministero della Salute Grant No. RF-2011-02350857 to G.T.

Funding

Research reported in this publication was supported in part by the Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ronald Ghossein.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Bin Xu and Nada Farhat contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, B., Farhat, N., Barletta, J.A. et al. Should subcentimeter non-invasive encapsulated, follicular variant of papillary thyroid carcinoma be included in the noninvasive follicular thyroid neoplasm with papillary-like nuclear features category?. Endocrine 59, 143–150 (2018). https://doi.org/10.1007/s12020-017-1484-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-017-1484-1

Keywords

Navigation