Advertisement

Molecular characterization of tumors meeting diagnostic criteria for the non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)

  • Christopher Pool
  • Vonn Walter
  • Darrin Bann
  • David Goldenberg
  • James Broach
  • Max Hennessy
  • Elizabeth Cottrill
  • Erik Washburn
  • Nicole Williams
  • Henry Crist
  • Yuka Imamura
  • Joshua I. WarrickEmail author
Original Article
  • 69 Downloads

Abstract

“Follicular variant” papillary thyroid carcinomas (FV-PTC) that do not histologically invade have a miniscule risk of metastasis, and thus been reclassified as a tumor of low malignant potential, the non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). There are few molecular studies of this tumor type. We performed gene expression analysis, by RNA sequencing, on a series of FV-PTCs, NIFTPs, and follicular adenomas. A training set comprised tumors from The Cancer Genome Atlas (TCGA) repository (n = 46), digital slides from which were reviewed and classified as invasive or non-invasive FV-PTC. A validation set comprised in-house NIFTPs, invasive FV-PTCs, and follicular adenomas (n = 26). In the training set, unsupervised clustering separated tumors into three distinct expression subtypes, which associated with invasion and characteristic molecular alterations. Specifically, the “BRAF-like” subtype was enriched in invasive FV-PTCs and tumors with BRAF V600E mutations. The “THADA-like” subtype was enriched in non-invasive tumors and those with rearrangements involving THADA. The “RAS-family-like” subtype included many invasive and non-invasive FV-PTCs and was enriched in tumors with mutations in RAS family genes. In the validation set, nearest centroid analysis classified all invasive FV-PTCs as “BRAF-like” and all follicular adenomas as either “RAS-like” or “THADA-like.” NIFTPs were the most molecularly diverse histologic type, with cases classified as “BRAF-like,” “THADA-like,” and “RAS-family-like.” In conclusion, tumors fitting criteria for NIFTP are molecularly diverse, making it difficult to diagnose them with molecular studies, likely including matrial from cytopathology samples.

Keywords

Thyroid cancer Follicular variant papillary thyroid carcinoma Non-invasive follicular thyroid neoplasm with papillary-like nuclear features BRAF-like RAS-like 

Notes

Acknowledgments

The authors would like to thank the Penn State Department of Pathology for the intradepartmental grant that funded this project.

Authors’ contributions

Christopher Pool, MD—data curation, methodology, writing of the original manuscript

Vonn Walter, PhD—data analysis, visualization, writing of the original manuscript

Darrin Bann, MD PhD—conceptualization, data curation, critical review of the final manuscript

David Goldenberg, MD—supervision, critical review of the final manuscript

James Broach, PhD—supervision, critical review of the final manuscript

Max Hennessy—data curation

Elizabeth Cottrill, MD—data curation, critical review of the final manuscript

Erik Washburn, MD—data curation

Nicole Williams, MD—critical review of the final manuscript

Henry Crist, MD—data curation, critical review of the final manuscript

Yuka Imamura, PhD—methodology, supervision, formal analysis, critical review of the final manuscript

Joshua I. Warrick, MD—conceptualization, data curation, formal analysis, writing original manuscript, critical review of the final manuscript

Funding

This study received financial support (intradepartmental research grant) from the Penn State Department of Pathology.

Compliance with ethical standards

This study was performed with approval from the Penn State College of Medicine Human Subjects Protection Office (Institutional Review Board). The study complies with all ethical standards as stated in the Ethical Responsibilities of Authors on the Virchows Archiv webpage (https://www.springer.com/medicine/pathology/journal/428). This study was entirely funded by departmental funds from the Department of Pathology at Penn State University College of Medicine.

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

428_2018_2512_MOESM1_ESM.pdf (562 kb)
ESM 1 (PDF 562 kb)
428_2018_2512_MOESM2_ESM.docx (21 kb)
ESM 2 (DOCX 21 kb)
428_2018_2512_MOESM3_ESM.docx (14 kb)
ESM 3 (DOCX 14 kb)
428_2018_2512_MOESM4_ESM.xlsx (4.9 mb)
ESM 4 (XLSX 4998 kb)

References

  1. 1.
    The Surveillance E, and End Results Program (SEER). The Surveillance, Epidemiology, and End Results Program (SEER). Thyroid Cancer Statistics, 1992–2012. Available at: https://seer.cancer.gov/statfacts/html/thyro.html. Accessed 04/3/2017
  2. 2.
    Kakudo K, Bai Y, Liu Z, Ozaki T (2012) Encapsulated papillary thyroid carcinoma, follicular variant: a misnomer. Pathol Int 62(3):155–160CrossRefGoogle Scholar
  3. 3.
    Liu J, Singh B, Tallini G, Carlson DL, Katabi N, Shaha A, Tuttle RM, Ghossein RA (2006) Follicular variant of papillary thyroid carcinoma: a clinicopathologic study of a problematic entity. Cancer 107(6):1255–1264CrossRefGoogle Scholar
  4. 4.
    Piana S, Frasoldati A, Di Felice E, Gardini G, Tallini G, Rosai J (2010) Encapsulated well-differentiated follicular-patterned thyroid carcinomas do not play a significant role in the fatality rates from thyroid carcinoma. Am J Surg Pathol 34(6):868–872CrossRefGoogle Scholar
  5. 5.
    Rivera M, Ricarte-Filho J, Knauf J, Shaha A, Tuttle M, Fagin JA, Ghossein RA (2010) 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):1191–1200CrossRefGoogle Scholar
  6. 6.
    Vivero M, Kraft S, Barletta JA (2013) Risk stratification of follicular variant of papillary thyroid carcinoma. Thyroid 23(3):273–279CrossRefGoogle Scholar
  7. 7.
    Widder S, Guggisberg K, Khalil M, Pasieka JL (2008) A pathologic re-review of follicular thyroid neoplasms: the impact of changing the threshold for the diagnosis of the follicular variant of papillary thyroid carcinoma. Surgery 144(1):80–85CrossRefGoogle Scholar
  8. 8.
    Nikiforov YE, Seethala RR, Tallini G, Baloch ZW, Basolo F, Thompson LDR, Barletta JA, Wenig BM, al Ghuzlan A, Kakudo K, Giordano TJ, Alves VA, Khanafshar E, Asa SL, el-Naggar AK, Gooding WE, Hodak SP, Lloyd RV, Maytal G, Mete O, Nikiforova MN, Nosé V, Papotti M, Poller DN, Sadow PM, Tischler AS, Tuttle RM, Wall KB, LiVolsi VA, Randolph GW, Ghossein RA (2016) Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol 2(8):1023–1029CrossRefGoogle Scholar
  9. 9.
    Lloyd RV, Osamura R, Kloppel G, Rosai J (2017) WHO Classification of tumours of endocrine organs. International Agency for Research on Cancer, LyonGoogle Scholar
  10. 10.
    Guerra A, Sapio MR, Marotta V et al (2011) Prevalence of RET/PTC rearrangement in benign and malignant thyroid nodules and its clinical application. Endocr J 58(1):31–38CrossRefGoogle Scholar
  11. 11.
    Kebebew E, Weng J, Bauer J, Ranvier G, Clark OH, Duh QY, Shibru D, Bastian B, Griffin A (2007) The prevalence and prognostic value of BRAF mutation in thyroid cancer. Ann Surg 246(3):466–471CrossRefGoogle Scholar
  12. 12.
    Drieschner N, Kerschling S, Soller JT, Rippe V, Belge G, Bullerdiek J, Nimzyk R (2007) A domain of the thyroid adenoma associated gene (THADA) conserved in vertebrates becomes destroyed by chromosomal rearrangements observed in thyroid adenomas. Gene 403(1–2):110–117CrossRefGoogle Scholar
  13. 13.
    Marques AR, Espadinha C, Catarino AL, Moniz S, Pereira T, Sobrinho LG, Leite V (2002) Expression of PAX8-PPAR gamma 1 rearrangements in both follicular thyroid carcinomas and adenomas. J Clin Endocrinol Metab 87(8):3947–3952Google Scholar
  14. 14.
    Clinkscales W, Ong A, Nguyen S, Harruff EE, Gillespie MB (2017) Diagnostic value of RAS mutations in indeterminate thyroid nodules. Otolaryngol Head Neck Surg 156(3):472–479CrossRefGoogle Scholar
  15. 15.
    Agrawal N, Akbani R, Aksoy BA, Ally A, Arachchi H, Asa SL, Auman JT, Balasundaram M, Balu S, Baylin SB, Behera M, Bernard B, Beroukhim R, Bishop JA, Black AD, Bodenheimer T, Boice L, Bootwalla MS, Bowen J, Bowlby R, Bristow CA, Brookens R, Brooks D, Bryant R, Buda E, Butterfield YSN, Carling T, Carlsen R, Carter SL, Carty SE, Chan TA, Chen AY, Cherniack AD, Cheung D, Chin L, Cho J, Chu A, Chuah E, Cibulskis K, Ciriello G, Clarke A, Clayman GL, Cope L, Copland JA, Covington K, Danilova L, Davidsen T, Demchok JA, DiCara D, Dhalla N, Dhir R, Dookran SS, Dresdner G, Eldridge J, Eley G, el-Naggar AK, Eng S, Fagin JA, Fennell T, Ferris RL, Fisher S, Frazer S, Frick J, Gabriel SB, Ganly I, Gao J, Garraway LA, Gastier-Foster JM, Getz G, Gehlenborg N, Ghossein R, Gibbs RA, Giordano TJ, Gomez-Hernandez K, Grimsby J, Gross B, Guin R, Hadjipanayis A, Harper HA, Hayes DN, Heiman DI, Herman JG, Hoadley KA, Hofree M, Holt RA, Hoyle AP, Huang FW, Huang M, Hutter CM, Ideker T, Iype L, Jacobsen A, Jefferys SR, Jones CD, Jones SJM, Kasaian K, Kebebew E, Khuri FR, Kim J, Kramer R, Kreisberg R, Kucherlapati R, Kwiatkowski DJ, Ladanyi M, Lai PH, Laird PW, Lander E, Lawrence MS, Lee D, Lee E, Lee S, Lee W, Leraas KM, Lichtenberg TM, Lichtenstein L, Lin P, Ling S, Liu J, Liu W, Liu Y, LiVolsi VA, Lu Y, Ma Y, Mahadeshwar HS, Marra MA, Mayo M, McFadden DG, Meng S, Meyerson M, Mieczkowski PA, Miller M, Mills G, Moore RA, Mose LE, Mungall AJ, Murray BA, Nikiforov YE, Noble MS, Ojesina AI, Owonikoko TK, Ozenberger BA, Pantazi A, Parfenov M, Park PJ, Parker JS, Paull EO, Pedamallu CS, Perou CM, Prins JF, Protopopov A, Ramalingam SS, Ramirez NC, Ramirez R, Raphael BJ, Rathmell WK, Ren X, Reynolds SM, Rheinbay E, Ringel MD, Rivera M, Roach J, Robertson AG, Rosenberg MW, Rosenthal M, Sadeghi S, Saksena G, Sander C, Santoso N, Schein JE, Schultz N, Schumacher SE, Seethala RR, Seidman J, Senbabaoglu Y, Seth S, Sharpe S, Shaw KRM, Shen JP, Shen R, Sherman S, Sheth M, Shi Y, Shmulevich I, Sica GL, Simons JV, Sinha R, Sipahimalani P, Smallridge RC, Sofia HJ, Soloway MG, Song X, Sougnez C, Stewart C, Stojanov P, Stuart JM, Sumer SO, Sun Y, Tabak B, Tam A, Tan D, Tang J, Tarnuzzer R, Taylor BS, Thiessen N, Thorne L, Thorsson V, Tuttle RM, Umbricht CB, van den Berg DJ, Vandin F, Veluvolu U, Verhaak RGW, Vinco M, Voet D, Walter V, Wang Z, Waring S, Weinberger PM, Weinhold N, Weinstein JN, Weisenberger DJ, Wheeler D, Wilkerson MD, Wilson J, Williams M, Winer DA, Wise L, Wu J, Xi L, Xu AW, Yang L, Yang L, Zack TI, Zeiger MA, Zeng D, Zenklusen JC, Zhao N, Zhang H, Zhang J, Zhang J(J), Zhang W, Zmuda E, Zou L (2014) Integrated genomic characterization of papillary thyroid carcinoma. Cell 159(3):676–690CrossRefGoogle Scholar
  16. 16.
    Yoo SK, Lee S, Kim SJ, Jee HG, Kim BA, Cho H, Song YS, Cho SW, Won JK, Shin JY, Park DJ, Kim JI, Lee KE, Park YJ, Seo JS (2016) Comprehensive analysis of the transcriptional and mutational landscape of follicular and papillary thyroid cancers. PLoS Genet 12(8):e1006239CrossRefGoogle Scholar
  17. 17.
    Giordano TJ, Kuick R, Thomas DG, Misek DE, Vinco M, Sanders D, Zhu Z, Ciampi R, Roh M, Shedden K, Gauger P, Doherty G, Thompson NW, Hanash S, Koenig RJ, Nikiforov YE (2005) Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. Oncogene 24(44):6646–6656CrossRefGoogle Scholar
  18. 18.
    R: A language and environment for statistical computing. [computer program]. Vienna, Austria.: R Foundation for Statistical Computing; 2014Google Scholar
  19. 19.
    Institute NC. Genomic Data Commons Data Portal. https://portal.gdc.cancer.gov. Accessed June 10 2017
  20. 20.
    Genome wide annotation for Human. org.Hs.eg.db [computer program]. 2017Google Scholar
  21. 21.
    Robinson MDMD, Smyth GK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26(1):139–140CrossRefGoogle Scholar
  22. 22.
    McCarthy DJCY, Smyth GK (2012) Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res 40(10):4299–4297CrossRefGoogle Scholar
  23. 23.
    sva: Surrogate Variable Analysis [computer program]. 2017Google Scholar
  24. 24.
    Wilkerson MD, Hayes DN (2013) ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics 26(12):1572–1573CrossRefGoogle Scholar
  25. 25.
    Dabney AR (2005) Classification of microarrays to nearest centroids. Bioinformatics 21(22):4148–4154CrossRefGoogle Scholar
  26. 26.
    Trapnell C, Pachter L, Salzberg SL (2009) TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25(9):1105–1111CrossRefGoogle Scholar
  27. 27.
    Law CW, Chen Y, Shi W, Smyth GK (2014) Voom: precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol 15(2):R29CrossRefGoogle Scholar
  28. 28.
    Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK (2015) Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43(7):e47CrossRefGoogle Scholar
  29. 29.
    Huang d W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4(1):44–57CrossRefGoogle Scholar
  30. 30.
    Huang DW, Sherman BT, Lempicki RA (2009) Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37(1):1–13CrossRefGoogle Scholar
  31. 31.
    Alexander EK, Kennedy GC, Baloch ZW, Cibas ES, Chudova D, Diggans J, Friedman L, Kloos RT, LiVolsi VA, Mandel SJ, Raab SS, Rosai J, Steward DL, Walsh PS, Wilde JI, Zeiger MA, Lanman RB, Haugen BR (2012) Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med 367(8):705–715CrossRefGoogle Scholar
  32. 32.
    Nikiforova MN, Wald AI, Roy S, Durso MB, Nikiforov YE (2013) Targeted next-generation sequencing panel (ThyroSeq) for detection of mutations in thyroid cancer. J Clin Endocrinol Metab 98(11):E1852–E1860CrossRefGoogle Scholar
  33. 33.
    Afirma. https://www.afirma.com/physicians. Accessed Nov 5 2017
  34. 34.
    pheatmap: Pretty Heatmaps [computer program]. Version 10.8. https://CRAN.R-project.org/package=pheatmap2015. Accessed Jan 15 2017
  35. 35.
    Nikiforov YE, Carty SE, Chiosea SI, Coyne C, Duvvuri U, Ferris RL, Gooding WE, Hodak SP, LeBeau SO, Ohori NP, Seethala RR, Tublin ME, Yip L, Nikiforova MN (2014) Highly accurate diagnosis of cancer in thyroid nodules with follicular neoplasm/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next-generation sequencing assay. Cancer 120(23):3627–3634CrossRefGoogle Scholar
  36. 36.
    Thyroseq. https://thyroseq.com/physicians. Accessed 11/5/2017
  37. 37.
    Ameziane-El-Hassani R, Schlumberger M, Dupuy C (2016) NADPH oxidases: new actors in thyroid cancer? Nat Rev Endocrinol 12(8):485–494CrossRefGoogle Scholar
  38. 38.
    Ameziane-El-Hassani R, Talbot M, de Souza Dos Santos MC et al (2015) NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation. Proc Natl Acad Sci U S A 112(16):5051–5056CrossRefGoogle Scholar
  39. 39.
    Raman P, Koenig RJ (2014) Pax-8-PPAR-gamma fusion protein in thyroid carcinoma. Nat Rev Endocrinol 10(10):616–623CrossRefGoogle Scholar
  40. 40.
    Xing M (2013) Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer 13(3):184–199CrossRefGoogle Scholar
  41. 41.
    Grivennikov S, Karin M (2008) Autocrine IL-6 signaling: a key event in tumorigenesis? Cancer Cell 13(1):7–9CrossRefGoogle Scholar
  42. 42.
    Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454(7203):436–444CrossRefGoogle Scholar
  43. 43.
    Chem KT, Rosai J (1977) Follicular variant of thyroid papillary carcinoma: a clinicopathologic study of six cases. Am J Surg Pathol 1(2):123–130CrossRefGoogle Scholar
  44. 44.
    Elsheikh TM, Asa SL, Chan JK et al (2008) Interobserver and intraobserver variation among experts in the diagnosis of thyroid follicular lesions with borderline nuclear features of papillary carcinoma. Am J Clin Pathol 130(5):736–744CrossRefGoogle Scholar
  45. 45.
    Hirokawa M, Carney JA, Goellner JR, DeLellis RA, Heffess CS, Katoh R, Tsujimoto M, Kakudo K (2002) Observer variation of encapsulated follicular lesions of the thyroid gland. Am J Surg Pathol 26(11):1508–1514CrossRefGoogle Scholar
  46. 46.
    Lloyd RV, Erickson LA, Casey MB, Lam KY, Lohse CM, Asa SL, Chan JKC, DeLellis RA, Harach HR, Kakudo K, LiVolsi VA, Rosai J, Sebo TJ, Sobrinho-Simoes M, Wenig BM, Lae ME (2004) Observer variation in the diagnosis of follicular variant of papillary thyroid carcinoma. Am J Surg Pathol 28(10):1336–1340CrossRefGoogle Scholar
  47. 47.
    Rippe V, Drieschner N, Meiboom M, Escobar HM, Bonk U, Belge G, Bullerdiek J (2003) Identification of a gene rearranged by 2p21 aberrations in thyroid adenomas. Oncogene 22(38):6111–6114CrossRefGoogle Scholar
  48. 48.
    Hang JF, Westra WH, Cooper DS, Ali SZ (2017) The impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features on the performance of the Afirma gene expression classifier. Cancer 125(9):683–691Google Scholar
  49. 49.
    Howitt BE, Jia Y, Sholl LM, Barletta JA (2013) Molecular alterations in partially-encapsulated or well-circumscribed follicular variant of papillary thyroid carcinoma. Thyroid 23(10):1256–1262CrossRefGoogle Scholar
  50. 50.
    Paulson VA, Shivdasani P, Angell TE, Cibas ES, Krane JF, Lindeman NI, Alexander EK, Barletta JA (2017) Noninvasive follicular thyroid neoplasm with papillary-like nuclear features accounts for more than half of “carcinomas” harboring RAS mutations. Thyroid 27(4):506–511CrossRefGoogle Scholar
  51. 51.
    Nikiforova MN, Mercurio S, Wald AI, Barbi de Moura M, Callenberg K, Santana-Santos L, Gooding WE, Yip L, Ferris RL, Nikiforov YE (2018) Analytical performance of the ThyroSeq v3 genomic classifier for cancer diagnosis in thyroid nodules. Cancer 124(8):1682–1690CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Christopher Pool
    • 1
  • Vonn Walter
    • 2
    • 3
    • 4
  • Darrin Bann
    • 1
  • David Goldenberg
    • 1
  • James Broach
    • 3
    • 4
  • Max Hennessy
    • 1
  • Elizabeth Cottrill
    • 1
  • Erik Washburn
    • 5
  • Nicole Williams
    • 5
  • Henry Crist
    • 5
  • Yuka Imamura
    • 4
  • Joshua I. Warrick
    • 5
    Email author
  1. 1.Department of Surgery, Division of Otolaryngology – Head and Neck SurgeryPenn State Milton S. Hershey Medical CenterHersheyUSA
  2. 2.Department of Public Health SciencesPenn State College of MedicineHersheyUSA
  3. 3.Department of Biochemistry and Molecular BiologyHersheyUSA
  4. 4.Institute for Personalized MedicinePenn State College of Medicine and Milton S. Hershey Medical CenterHersheyUSA
  5. 5.Department of PathologyPenn State College of Medicine and Milton S. Hershey Medical CenterHersheyUSA

Personalised recommendations