Outcome and molecular characteristics of non-invasive encapsulated follicular variant of papillary thyroid carcinoma with oncocytic features
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In 2016, non-invasive encapsulated follicular variant of papillary thyroid carcinoma (NI-EFVPTC) was renamed as noninvasive thyroid follicular neoplasm with papillary-like nuclear features (NIFTP). However, as the study cohort did not mention tumors with oncocytic features, such lesions are still labeled by some as FVPTC. It is therefore crucial to evaluate the outcome and molecular profile of oncocytic NI-EFVPTC.
A multi-institutional clinico-pathologic review was conducted to select 61 patients having oncocytic NI-EFVPTC. A detailed molecular profile was carried out in 15 patients.
Oncocytic NI-EFVPTCs predominantly affected women in their 50s. There was no distant metastasis, lymph node metastases, or structural recurrence in the entire cohort. Among patients with ≥5 years of FU, all 33 individuals did not recur with a median FU of 10.2 years. Oncocytic NI-EFVPTC commonly had RAS (33%) mutations, a high frequency of mitochondrial DNA mutations (67%) and multiple chromosomal gains/losses (53%). No fusion genes were detected.
Oncocytic NI-EFVPTC, when stringently selected for, lacks metastasis at presentation and follows an extremely indolent clinical course, even when treated conservatively with lobectomy alone without RAI therapy. These tumors share a similar mutational profile as NIFTP, FVPTC, and follicular neoplasm and are predominantly RAS-related. Like Hurthle cell neoplasms, they harbor a high frequency of mitochondrial DNA mutations, which contribute to the oncocytic cytomorphology. However, they lack the widespread chromosomal alterations observed in Hurthle cell carcinoma. Consideration should be given to include oncocytic NI-EFVPTCs as NIFTP in order to avoid overtreatment of these highly indolent tumors.
KeywordsEncapsulated follicular variant Papillary thyroid carcinoma Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) RAS Oncocytic
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. Research reported in this publication was also supported in part by an Italian Government-Ministero della Salute Grant No. RF-2011-02350857 (to G.T.)
Compliance with ethical standards
Conflict of interest
All authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
- 3.C.K. Jung, M.P. Little, J.H. Lubin, A.V. Brenner, S.A. Wells Jr., A.J. Sigurdson, Y.E. Nikiforov, 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 CrossRefGoogle Scholar
- 4.R.V. Lloyd, R.Y. Osamura, G. Kloppel, J. Rosai. WHO classification of tumours of endocrine organs. (International Agency for Research on Cancer (IARC), Lyon), 2017)Google Scholar
- 5.Y.E. Nikiforov, R.R. Seethala, G. Tallini, Z.W. Baloch, F. Basolo, L.D. Thompson, J.A. Barletta, B.M. Wenig, A. Al Ghuzlan, K. Kakudo, T.J. Giordano, V.A. Alves, E. Khanafshar, S.L. Asa, A.K. El-Naggar, W.E. Gooding, S.P. Hodak, R.V. Lloyd, G. Maytal, O. Mete, M.N. Nikiforova, V. Nose, M. Papotti, D.N. Poller, P.M. Sadow, A.S. Tischler, R.M. Tuttle, K.B. Wall, V.A. LiVolsi, G.W. Randolph, R.A. Ghossein, 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 CrossRefGoogle Scholar
- 7.D.N. Johnson, L.V. Furtado, B.C. Long, C.J. Zhen, M. Wurst, I. Mujacic, S. Kadri, J.P. Segal, T. Antic, N.A. Cipriani, Noninvasive follicular thyroid neoplasms with papillary-like nuclear features are genetically and biologically similar to adenomatous nodules and distinct from papillary thyroid carcinomas with extensive follicular growth. Arch. Pathol. Lab. Med. 142(7), 838–850 (2018). https://doi.org/10.5858/arpa.2017-0118-OA CrossRefGoogle Scholar
- 9.R.V. Lloyd, S.L. Asa, V.A. LiVolsi, P.M. Sadow, A.S. Tischler, R.A. Ghossein, R.M. Tuttle, Y.E. Nikiforov, The evolving diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Hum. Pathol. 74, 1–4 (2018). https://doi.org/10.1016/j.humpath.2017.12.027 CrossRefGoogle Scholar
- 10.S.J. Johnson, T.J. Stephenson, D.N. Poller, NIFTP addendum to the RCPath Dataset for thyroid cancer histopathology reports. http://www.ukeps.com/docs/niftp.pdf (2016).
- 11.I. Ganly, J. Ricarte Filho, S. Eng, R. Ghossein, L.G. Morris, Y. Liang, N. Socci, K. Kannan, Q. Mo, J.A. Fagin, T.A. Chan, Genomic dissection of Hurthle cell carcinoma reveals a unique class of thyroid malignancy. J. Clin. Endocrinol. Metab. 98(5), E962–E972 (2013). https://doi.org/10.1210/jc.2012-3539 CrossRefGoogle Scholar
- 12.J. Rosai, R.A. DeLellis, M.L. Carcangiu, W.J. Frable, T. Giovanni. 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
- 13.D.T. Cheng, T.N. Mitchell, A. Zehir, R.H. Shah, R. Benayed, A. Syed, R. Chandramohan, Z.Y. Liu, H.H. Won, S.N. Scott, A.R. Brannon, C. O’Reilly, J. Sadowska, J. Casanova, A. Yannes, J.F. Hechtman, J. Yao, W. Song, D.S. Ross, A. Oultache, S. Dogan, L. Borsu, M. Hameed, K. Nafa, M.E. Arcila, M. Ladanyi, M.F. Berger, Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J. Mol. Diagn. 17(3), 251–264 (2015). https://doi.org/10.1016/j.jmoldx.2014.12.006 CrossRefGoogle Scholar
- 14.L.G. Morris, R. Chandramohan, L. West, A. Zehir, D. Chakravarty, D.G. Pfister, R.J. Wong, N.Y. Lee, E.J. Sherman, S.S. Baxi, I. Ganly, B. Singh, J.P. Shah, A.R. Shaha, J.O. Boyle, S.G. Patel, B.R. Roman, C.A. Barker, S.M. McBride, T.A. Chan, S. Dogan, D.M. Hyman, M.F. Berger, D.B. Solit, N. Riaz, A.L. Ho. The molecular landscape of recurrent and metastatic head and neck cancers: insights from a precision oncology sequencing platform. JAMA Oncol. 3(2), 244–255 (2017). https://doi.org/10.1001/jamaoncol.2016.1790
- 17.I. Ganly, V. Makarov, S. Deraje, Y. Dong, E. Reznik, V. Seshan, G. Nanjangud, S. Eng, P. Bose, F. Kuo, L.G.T. Morris, I. Landa, P.B. Carrillo Albornoz, N. Riaz, Y.E. Nikiforov, K. Patel, C. Umbricht, M. Zeiger, E. Kebebew, E. Sherman, R. Ghossein, J.A. Fagin, T.A. Chan, Integrated genomic analysis of hurthle cell cancer reveals oncogenic drivers, recurrent mitochondrial mutations, and unique chromosomal landscapes. Cancer Cell. 34(2), 256–270.e255 (2018). https://doi.org/10.1016/j.ccell.2018.07.002 CrossRefGoogle Scholar
- 19.E. Reznik, Q. Wang, K. La, N. Schultz, C. Sander, Mitochondrial respiratory gene expression is suppressed in many cancers. eLife 6, PMID: 28099114 (2017). https://doi.org/10.7554/eLife.21592
- 20.B.R. Haugen, A.M. Sawka, E.K. Alexander, K.C. Bible, P. Caturegli, G.M. Doherty, S.J. Mandel, J.C. Morris, A. Nassar, F. Pacini, M. Schlumberger, K. Schuff, S.I. Sherman, H. Somerset, J.A. Sosa, D.L. Steward, L. Wartofsky, M.D. Williams, American Thyroid Association Guidelines on the Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of Encapsulated Follicular Variant Papillary Thyroid Carcinoma Without Invasion to Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features. Thyroid. 27(4), 481–483 (2017). https://doi.org/10.1089/thy.2016.0628 CrossRefGoogle Scholar
- 21.B.R.M. Haugen, E.K. Alexander, K.C. Bible, G. Doherty, S.J. Mandel, Y.E. Nikiforov, F. Pacini, G. Randolph, A. Sawka, M. Schlumberger, K.G. Schuff, S.I. Sherman, J.A. Sosa, D. Steward, R.M.M. Tuttle, L. Wartofsky, 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 CrossRefGoogle Scholar
- 24.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 CrossRefGoogle Scholar
- 25.M. Rivera, J. Ricarte-Filho, J. Knauf, A. Shaha, M. Tuttle, J.A. Fagin, R.A. Ghossein, 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 CrossRefGoogle Scholar
- 26.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 CrossRefGoogle Scholar
- 27.E. Cerami, J. Gao, U. Dogrusoz, B.E. Gross, S.O. Sumer, B.A. Aksoy, A. Jacobsen, C.J. Byrne, M.L. Heuer, E. Larsson, Y. Antipin, B. Reva, A.P. Goldberg, C. Sander, N. Schultz, The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2(5), 401–404 (2012). https://doi.org/10.1158/2159-8290.cd-12-0095 CrossRefGoogle Scholar
- 28.G. Tallini, A. Hsueh, S. Liu, G. Garcia-Rostan, M.R. Speicher, D.C. Ward, Frequent chromosomal DNA unbalance in thyroid oncocytic (Hurthle cell) neoplasms detected by comparative genomic hybridization. Lab. Invest. 79(5), 547–555 (1999)Google Scholar
- 29.J. Gao, B.A. Aksoy, U. Dogrusoz, G. Dresdner, B. Gross, S.O. Sumer, Y. Sun, A. Jacobsen, R. Sinha, E. Larsson, E. Cerami, C. Sander, N. Schultz, Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6(269), pl1 (2013). https://doi.org/10.1126/scisignal.2004088 CrossRefGoogle Scholar
- 31.E. Bonora, A.M. Porcelli, G. Gasparre, A. Biondi, A. Ghelli, V. Carelli, A. Baracca, G. Tallini, A. Martinuzzi, G. Lenaz, M. Rugolo, G. Romeo, Defective oxidative phosphorylation in thyroid oncocytic carcinoma is associated with pathogenic mitochondrial DNA mutations affecting complexes I and III. Cancer Res. 66(12), 6087–6096 (2006). https://doi.org/10.1158/0008-5472.can-06-0171 CrossRefGoogle Scholar
- 32.G. Gasparre, A.M. Porcelli, E. Bonora, L.F. Pennisi, M. Toller, L. Iommarini, A. Ghelli, M. Moretti, C.M. Betts, G.N. Martinelli, A.R. Ceroni, F. Curcio, V. Carelli, M. Rugolo, G. Tallini, G. Romeo, Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors. Proc. Natl Acad. Sci. USA 104(21), 9001–9006 (2007). https://doi.org/10.1073/pnas.0703056104 CrossRefGoogle Scholar
- 33.V. Maximo, T. Botelho, J. Capela, P. Soares, J. Lima, A. Taveira, T. Amaro, A.P. Barbosa, A. Preto, H.R. Harach, D. Williams, M. Sobrinho-Simoes, Somatic and germline mutation in GRIM-19, a dual function gene involved in mitochondrial metabolism and cell death, is linked to mitochondrion-rich (Hurthle cell) tumours of the thyroid. Br. J. Cancer 92(10), 1892–1898 (2005). https://doi.org/10.1038/sj.bjc.6602547 CrossRefGoogle Scholar
- 34.N. Wada, Q.Y. Duh, D. Miura, L. Brunaud, M.G. Wong, O.H. Clark, Chromosomal aberrations by comparative genomic hybridization in hurthle cell thyroid carcinomas are associated with tumor recurrence. J. Clin. Endocrinol. Metab. 87(10), 4595–4601 (2002). https://doi.org/10.1210/jc.2002-020339 CrossRefGoogle Scholar
- 35.I. Ganly, L. Wang, R.M. Tuttle, N. Katabi, G.A. Ceballos, H.R. Harach, R. Ghossein, 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 CrossRefGoogle Scholar