Can TP53-mutant follicular adenoma be a precursor of anaplastic thyroid carcinoma?

in Endocrine-Related Cancer
View More View Less
  • 1 Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  • | 2 Division of Endocrine Surgery, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  • | 3 Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

Correspondence should be addressed to Y E Nikiforov: nikiforovye@upmc.edu
Restricted access

Mutations of the TP53 tumor suppressor gene are highly prevalent in thyroid anaplastic carcinomas (AC) but are also reported in some well-differentiated cancers and even in benign adenomas. The natural history of TP53-mutant adenomas and whether they may represent a precursor for well-differentiated cancer or AC is largely unknown. Similarly, the frequency of TP53 mutations in thyroid nodules found on routine molecular analysis of fine-needle aspiration (FNA) samples is not established. A database on 44,510 FNA samples from thyroid nodules with predominantly indeterminate cytology tested using ThyroSeq v3 was reviewed to identify TP53-mutant cases and analyze their genetic profile and available clinicopathological findings. Among 260 (0.6%) selected thyroid nodules, 36 had an isolated TP53 mutation and 224 carried a combination of TP53 with other genetic alterations. No significant difference was observed between these groups with respect to patient age, gender, nodule size, and spectrum of TP53 mutations. Histopathologically, 86% of the resected nodules with isolated TP53 mutations were benign (mostly adenomas), whereas 82% of nodules carrying TP53 mutations co-occurring with other alterations were cancers (P = 0.001), including de-differentiated AC. TP53-mutant benign tumors and well-differentiated cancers often had scattered single neoplastic cells with bizarre nuclei resembling those comprising AC. Our study demonstrates that a small but distinct proportion of thyroid nodules carry a TP53 mutation, either as a single genetic event or in combination with other alterations. While the latter is mostly cancers prone to dedifferentiation, there is at least a theoretical possibility that TP53-mutated adenomas may represent a precursor for such cancers, including AC.

 

Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 848 848 159
Full Text Views 53 53 6
PDF Downloads 87 87 8
  • Albores-Saavedra J, Hernandez M, Sanchez-Sosa S, Simpson K, Angeles A & Henson DE 2007 Histologic variants of papillary and follicular carcinomas associated with anaplastic spindle and giant cell carcinomas of the thyroid: an analysis of rhabdoid and thyroglobulin inclusions. American Journal of Surgical Pathology 31 7297 36. (https://doi.org/10.1097/01.pas.0000213417.00386.74)

    • Search Google Scholar
    • Export Citation
  • Aldinger KA, Samaan NA, Ibanez M & Hill Jr CS 1978 Anaplastic carcinoma of the thyroid: a review of 84 cases of spindle and giant cell carcinoma of the thyroid. Cancer 41 226722 75. (https://doi.org/10.1002/1097-0142(197806)41:6<2267::aid-cncr2820410627>3.0.co;2-7)

    • Search Google Scholar
    • Export Citation
  • Asakawa H & Kobayashi T 2002 Multistep carcinogenesis in anaplastic thyroid carcinoma: a case report. Pathology 34 949 7. (https://doi.org/10.1080/00313020120105732)

    • Search Google Scholar
    • Export Citation
  • Asioli S, Erickson LA, Righi A, Jin L, Volante M, Jenkins S, Papotti M, Bussolati G & Lloyd RV 2010 Poorly differentiated carcinoma of the thyroid: validation of the Turin proposal and analysis of IMP3 expression. Modern Pathology 23 126912 78. (https://doi.org/10.1038/modpathol.2010.117)

    • Search Google Scholar
    • Export Citation
  • Borowczyk M, Szczepanek-Parulska E, Debicki S, Budny B, Verburg FA, Filipowicz D, Wieckowska B, Janicka-Jedynska M, Gil L & Ziemnicka K et al.2019 Differences in mutational profile between follicular thyroid carcinoma and follicular thyroid adenoma identified using next generation sequencing. International Journal of Molecular Sciences 20 3126. (https://doi.org/10.3390/ijms20133126)

    • Search Google Scholar
    • Export Citation
  • Bouaoun L, Sonkin D, Ardin M, Hollstein M, Byrnes G, Zavadil J & Olivier M 2016 TP53 variations in human cancers: new lessons from the IARC TP53 database and genomics data. Human Mutation 37 8658 76. (https://doi.org/10.1002/humu.23035)

    • Search Google Scholar
    • Export Citation
  • Cancer Genome Atlas Research Network 2014 Integrated genomic characterization of papillary thyroid carcinoma. Cell 159 676690.

  • Chen XX, Zhong Q, Liu Y, Yan SM, Chen ZH, Jin SZ, Xia TL, Li RY, Zhou AJ & Su Z et al.2017 Genomic comparison of esophageal squamous cell carcinoma and its precursor lesions by multi-region whole-exome sequencing. Nature Communications 8 524. (https://doi.org/10.1038/s41467-017-00650-0)

    • Search Google Scholar
    • Export Citation
  • Chen H, Luthra R, Routbort MJ, Patel KP, Cabanillas ME, Broaddus RR & Williams MD 2018 Molecular profile of advanced thyroid carcinomas by next-generation sequencing: characterizing tumors beyond diagnosis for targeted therapy. Molecular Cancer Therapeutics 17 15751584. (https://doi.org/10.1158/1535-7163.MCT-17-0871)

    • Search Google Scholar
    • Export Citation
  • Chu YH, Wirth LJ, Farahani AA, Nose V, Faquin WC, Dias-Santagata D & Sadow PM 2020 Clinicopathologic features of kinase fusion-related thyroid carcinomas: an integrative analysis with molecular characterization. Modern Pathology 33 24582472. (https://doi.org/10.1038/s41379-020-0638-5)

    • Search Google Scholar
    • Export Citation
  • Cracolici V, Ritterhouse LL, Segal JP, Puranik R, Wanjari P, Kadri S, Parilla M & Cipriani NA 2020 Follicular thyroid neoplasms: comparison of clinicopathologic and molecular features of atypical adenomas and follicular thyroid carcinomas. American Journal of Surgical Pathology 44 881892. (https://doi.org/10.1097/PAS.0000000000001489)

    • Search Google Scholar
    • Export Citation
  • de la Fouchardiere C, Decaussin-Petrucci M, Berthiller J, Descotes F, Lopez J, Lifante JC, Peix JL, Giraudet AL, Delahaye A & Masson S et al.2018 Predictive factors of outcome in poorly differentiated thyroid carcinomas. European Journal of Cancer 92 4047. (https://doi.org/10.1016/j.ejca.2017.12.027)

    • Search Google Scholar
    • Export Citation
  • Donehower LA, Soussi T, Korkut A, Liu Y, Schultz A, Cardenas M, Li X, Babur O, Hsu TK & Lichtarge O et al.2019 Integrated analysis of TP53 gene and pathway alterations in the cancer genome Atlas. Cell Reports 28 13701384.e5. (https://doi.org/10.1016/j.celrep.2019.07.001)

    • Search Google Scholar
    • Export Citation
  • Duan H, Liu X, Ren X, Zhang H, Wu H & Liang Z 2019 Mutation profiles of follicular thyroid tumors by targeted sequencing. Diagnostic Pathology 14 39. (https://doi.org/10.1186/s13000-019-0817-1)

    • Search Google Scholar
    • Export Citation
  • Evangelisti C, De Biase D, Kurelac I, Ceccarelli C, Prokisch H, Meitinger T, Caria P, Vanni R, Romeo G & Tallini G et al.2015 A mutation screening of oncogenes, tumor suppressor gene TP53 and nuclear encoded mitochondrial complex I genes in oncocytic thyroid tumors. BMC Cancer 15 157. (https://doi.org/10.1186/s12885-015-1122-3)

    • Search Google Scholar
    • Export Citation
  • Fagin JA, Matsuo K, Karmakar A, Chen DL, Tang SH & Koeffler HP 1993 High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. Journal of Clinical Investigation 91 1791 84. (https://doi.org/10.1172/JCI116168)

    • Search Google Scholar
    • Export Citation
  • Ganly I, Makarov V, Deraje S, Dong Y, Reznik E, Seshan V, Nanjangud G, Eng S, Bose P & Kuo F et al.2018 Integrated genomic analysis of Hurthle cell cancer reveals oncogenic drivers, recurrent mitochondrial mutations, and unique chromosomal landscapes. Cancer Cell 34 256–270.e5. (https://doi.org/10.1016/j.ccell.2018.07.002)

    • Search Google Scholar
    • Export Citation
  • Gerber TS, Schad A, Hartmann N, Springer E, Zechner U & Musholt TJ 2018 Targeted next-generation sequencing of cancer genes in poorly differentiated thyroid cancer. Endocrine Connections 7 4755. (https://doi.org/10.1530/EC-17-0290)

    • Search Google Scholar
    • Export Citation
  • Gopal RK, Kubler K, Calvo SE, Polak P, Livitz D, Rosebrock D, Sadow PM, Campbell B, Donovan SE & Amin S et al.2018 Widespread chromosomal losses and mitochondrial DNA alterations as genetic drivers in Hurthle cell carcinoma. Cancer Cell 34 242.e5–255.e5. (https://doi.org/10.1016/j.ccell.2018.06.013)

    • Search Google Scholar
    • Export Citation
  • Grebe SK, Mciver B, Hay ID, Wu PS, Maciel LM, Drabkin HA, Goellner JR, Grant CS, Jenkins RB & Eberhardt NL 1997 Frequent loss of heterozygosity on chromosomes 3p and 17p without VHL or p53 mutations suggests involvement of unidentified tumor suppressor genes in follicular thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 82 368436 91. (https://doi.org/10.1210/jcem.82.11.4352)

    • Search Google Scholar
    • Export Citation
  • Hatakeyama H, Hoshino K, Mizoguchi K, Suzuki T, Hatanaka KC, Yamaya Y, Kano S, Mizumachi T & Homma A 2017 Atypical adenoma of the thyroid diagnosed as anaplastic cancer by cytopathology. Diagnostic Cytopathology 45 928933. (https://doi.org/10.1002/dc.23751)

    • Search Google Scholar
    • Export Citation
  • Hirokawa M, Sugitani I, Kakudo K, Sakamoto A, Higashiyama T, Sugino K, Toda K, Ogasawara S, Yoshimoto S & Hasegawa Y et al.2016 Histopathological analysis of anaplastic thyroid carcinoma cases with long-term survival: a report from the Anaplastic Thyroid Carcinoma Research Consortium of Japan. Endocrine Journal 63 44144 7. (https://doi.org/10.1507/endocrj.EJ15-0705)

    • Search Google Scholar
    • Export Citation
  • Hundahl SA, Cady B, Cunningham MP, Mazzaferri E, Mckee RF, Rosai J, Shah JP, Fremgen AM, Stewart AK & Holzer S 2000 Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the united states during 1996. U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on cancer patient care evaluation study. Cancer 89 2022 17. (https://doi.org/10.1002/1097-0142(20000701)89:1<202::aid-cncr27>3.0.co;2-a)

    • Search Google Scholar
    • Export Citation
  • Ibrahimpasic T, Ghossein RM, Shah JP & Ganly I 2019 Poorly differentiated carcinoma of the thyroid gland: current status and future prospects. Thyroid 29 311321. (https://doi.org/10.1089/thy.2018.0509)

    • Search Google Scholar
    • Export Citation
  • Ito T, Seyama T, Mizuno T, Tsuyama N, Hayashi Y, Dohi K, Nakamura N & Akiyama M 1993 Genetic alterations in thyroid tumor progression: association with p53 gene mutations. Japanese Journal of Cancer Research 84 5265 31. (https://doi.org/10.1111/j.1349-7006.1993.tb00171.x)

    • Search Google Scholar
    • Export Citation
  • Jung SH, Kim MS, Jung CK, Park HC, Kim SY, Liu J, Bae JS, Lee SH, Kim TM & Lee SH et al.2016 Mutational burdens and evolutionary ages of thyroid follicular adenoma are comparable to those of follicular carcinoma. Oncotarget 7 6963869648. (https://doi.org/10.18632/oncotarget.11922)

    • Search Google Scholar
    • Export Citation
  • Kebebew E, Greenspan FS, Clark OH, Woeber KA & Mcmillan A 2005 Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer 103 1330133 5. (https://doi.org/10.1002/cncr.20936)

    • Search Google Scholar
    • Export Citation
  • Landa I, Ibrahimpasic T, Boucai L, Sinha R, Knauf JA, Shah RH, Dogan S, Ricarte-Filho JC, Krishnamoorthy GP & Xu B et al.2016 Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. Journal of Clinical Investigation 126 105210 66. (https://doi.org/10.1172/JCI85271)

    • Search Google Scholar
    • Export Citation
  • Latteyer S, Tiedje V, Konig K, Ting S, Heukamp LC, Meder L, Schmid KW, Fuhrer D & Moeller LC 2016 Targeted next-generation sequencing for TP53, RAS, BRAF, ALK and NF1 mutations in anaplastic thyroid cancer. Endocrine 54 733741. (https://doi.org/10.1007/s12020-016-1080-9)

    • Search Google Scholar
    • Export Citation
  • Lin JD, Chao TC & Hsueh C 2007 Clinical characteristics of poorly differentiated thyroid carcinomas compared with those of classical papillary thyroid carcinomas. Clinical Endocrinology 66 22422 8. (https://doi.org/10.1111/j.1365-2265.2006.02712.x)

    • Search Google Scholar
    • Export Citation
  • Lloyd RV, Osamura RY, Klöppel G, Rosai Geds) 2017 World Health Organization Classification of Tumours of Endocrine Organs. Lyon: IARC Press.

  • Nakamura T, Yana I, Kobayashi T, Shin E, Karakawa K, Fujita S, Miya A, Mori T, Nishisho I & Takai S 1992 p53 gene mutations associated with anaplastic transformation of human thyroid carcinomas. Japanese Journal of Cancer Research 83 1293129 8. (https://doi.org/10.1111/j.1349-7006.1992.tb02761.x)

    • Search Google Scholar
    • Export Citation
  • 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 16821690. (https://doi.org/10.1002/cncr.31245)

    • Search Google Scholar
    • Export Citation
  • Oishi N, Kondo T, Ebina A, Sato Y, Akaishi J, Hino R, Yamamoto N, Mochizuki K, Nakazawa T & Yokomichi H et al.2017 Molecular alterations of coexisting thyroid papillary carcinoma and anaplastic carcinoma: identification of tert mutation as an independent risk factor for transformation. Modern Pathology 30 15271537. (https://doi.org/10.1038/modpathol.2017.75)

    • Search Google Scholar
    • Export Citation
  • Patel KN & Shaha AR 2006 Poorly differentiated and anaplastic thyroid cancer. Cancer Control 13 1191 28. (https://doi.org/10.1177/107327480601300206)

    • Search Google Scholar
    • Export Citation
  • Pavelic K, Dedivitis RA, Kapitanovic S, Cacev T, Guirado CR, Danic D, Radosevic S, Brkic K, Pegan B & Krizanac S et al.2006 Molecular genetic alterations of FHIT and p53 genes in benign and malignant thyroid gland lesions. Mutation Research 599 4557. (https://doi.org/10.1016/j.mrfmmm.2006.01.021)

    • Search Google Scholar
    • Export Citation
  • Pearce TM, Nikiforova MN & Roy S 2019 Interactive browser-based genomics data visualization tools for translational and clinical laboratory applications. Journal of Molecular Diagnostics 21 985993. (https://doi.org/10.1016/j.jmoldx.2019.06.005)

    • Search Google Scholar
    • Export Citation
  • Pozdeyev N, Gay LM, Sokol ES, Hartmaier R, Deaver KE, Davis S, French JD, Borre PV, Labarbera DV & Tan AC et al.2018 Genetic analysis of 779 advanced differentiated and anaplastic thyroid cancers. Clinical Cancer Research 24 30593068. (https://doi.org/10.1158/1078-0432.CCR-18-0373)

    • Search Google Scholar
    • Export Citation
  • Robles AI, Traverso G, Zhang M, Roberts NJ, Khan MA, Joseph C, Lauwers GY, Selaru FM, Popoli M & Pittman ME et al.2016 Whole-exome sequencing analyses of inflammatory bowel disease-associated colorectal cancers. Gastroenterology 150 9319 43. (https://doi.org/10.1053/j.gastro.2015.12.036)

    • Search Google Scholar
    • Export Citation
  • Santana NO, Lerario AM, Schmerling CK, Marui S, Alves VAF, Hoff AO, Kopp P & Danilovic DLS 2020 Molecular profile of Hürthle cell carcinomas: recurrent mutations in the Wnt/β-catenin pathway. European Journal of Endocrinology 183 647656. (https://doi.org/10.1530/EJE-20-0597)

    • Search Google Scholar
    • Export Citation
  • Siegel RL, Miller KD & Jemal A 2019 Cancer statistics, 2019. CA: A Cancer Journal for Clinicians 69 734. (https://doi.org/10.3322/caac.21551)

    • Search Google Scholar
    • Export Citation
  • Siironen P, Hagstrom J, Maenpaa HO, Louhimo J, Heikkila A, Heiskanen I, Arola J & Haglund C 2010 Anaplastic and poorly differentiated thyroid carcinoma: therapeutic strategies and treatment outcome of 52 consecutive patients. Oncology 79 40040 8. (https://doi.org/10.1159/000322640)

    • Search Google Scholar
    • Export Citation
  • Smida J, Zitzelsberger H, Kellerer AM, Lehmann L, Minkus G, Negele T, Spelsberg F, Hieber L, Demidchik EP & Lengfelder E et al.1997 p53 mutations in childhood thyroid tumours from Belarus and in thyroid tumours without radiation history. International Journal of Cancer 73 80280 7. (https://doi.org/10.1002/(sici)1097-0215(19971210)73:6<802::aid-ijc5>3.0.co;2-6)

    • Search Google Scholar
    • Export Citation
  • Stachler MD, Taylor-Weiner A, Peng S, Mckenna A, Agoston AT, Odze RD, Davison JM, Nason KS, Loda M & Leshchiner I et al.2015 Paired exome analysis of Barrett’s esophagus and adenocarcinoma. Nature Genetics 47 104710 55. (https://doi.org/10.1038/ng.3343)

    • Search Google Scholar
    • Export Citation
  • Tiedje V, Ting S, Herold T, Synoracki S, Latteyer S, Moeller LC, Zwanziger D, Stuschke M, Fuehrer D & Schmid KW 2017 NGS based identification of mutational hotspots for targeted therapy in anaplastic thyroid carcinoma. Oncotarget 8 4261342620. (https://doi.org/10.18632/oncotarget.17300)

    • Search Google Scholar
    • Export Citation
  • Tzen CY, Huang YW & Fu YS 2003 Is atypical follicular adenoma of the thyroid a pre-invasive malignancy? Human Pathology 34 66666 9. (https://doi.org/10.1016/s0046-8177(0300241-7)

    • Search Google Scholar
    • Export Citation
  • Venkatesh YS, Ordonez NG, Schultz PN, Hickey RC, Goepfert H & Samaan NA 1990 Anaplastic carcinoma of the thyroid. A clinicopathologic study of 121 cases. Cancer 66 3213 3 0. (https://doi.org/10.1002/1097-0142(19900715)66:2<321::aid-cncr2820660221>3.0.co;2-a)

    • Search Google Scholar
    • Export Citation
  • Xu B, Fuchs T, Dogan S, Landa I, Katabi N, Fagin JA, Tuttle RM, Sherman E, Gill AJ & Ghossein R 2020 Dissecting anaplastic thyroid carcinoma: a comprehensive clinical, histologic, immunophenotypic, and molecular study of 360 cases. Thyroid 30 15051517. (https://doi.org/10.1089/thy.2020.0086)

    • Search Google Scholar
    • Export Citation
  • Yoo SK, Lee S, Kim SJ, Jee HG, Kim BA, Cho H, Song YS, Cho SW, Won JK & Shin JY et al.2016 Comprehensive analysis of the transcriptional and mutational landscape of follicular and papillary thyroid cancers. PLoS Genetics 12 e1006239. (https://doi.org/10.1371/journal.pgen.1006239)

    • Search Google Scholar
    • Export Citation
  • Zedenius J, Auer G, Backdahl M, Falkmer U, Grimelius L, Lundell G & Wallin G 1992 Follicular tumors of the thyroid gland: diagnosis, clinical aspects and nuclear DNA analysis. World Journal of Surgery 16 5895 94. (https://doi.org/10.1007/BF02067329)

    • Search Google Scholar
    • Export Citation
  • Zedenius J, Larsson C, Wallin G, Backdahl M, Aspenblad U, Hoog A, Borresen AL & Auer G 1996 Alterations of p53 and expression of WAF1/p21 in human thyroid tumors. Thyroid 6 19. (https://doi.org/10.1089/thy.1996.6.1)

    • Search Google Scholar
    • Export Citation