Clinical and morphological features of thyroid tumors with mutations in the NTRK, RAS, BRAF, RET genes

Despite the rather favorable clinical course of thyroid tumors, the issue of timely and high-quality diagnosis is still relevant. Due to the development of personalized treatment in medicine and the emergence of drugs that target specific mutations, timely detection of these mutations is very important. The pathologist should be focused on the search for certain morphological markers that suggest the presence of certain mutations in tumor cells. To narrow the differential diagnostic search, it is important to know the mechanisms of development of key mutations, mutually exclusive mutations, to have information about the clinical course of the disease. Based on these data, the next step will be more specific diagnostics (IHC, molecular genetic methods). Based on the analysis of literature data, it was possible to identify some distinctive morphological signs that can help the pathologist to suspect the presence of a particular mutation in the tumor. For mutations in the NTRK genes, such signs are the follicular variant of papillary cancer, nuclear pseudo-inclusions, presence of an oncocytic component, metastases, and the absence of a solid component. For the assumption of RAS mutations, attention paid to tumors of the follicular structure with an aggressive clinical course. The young age of the patient, metastases to the lymph nodes, and cancer of the thyroid gland of the classic papillary structure will allow one to assume the presence of a mutation in the RET gene. The BRAF mutation is characterized by specific cellular changes (pseudo-inclusions in the nuclei, the presence of plump cells or cells with sickle-shaped nuclei) in a thyroid cancer with a classic papillary structure.

1. Kaprin A.D., Starinskii V.V. Zlokachestvennye novoobrazovaniya v Rossii v 2015 godu (zabolevaemost' i smertnost') - M.: MNIOI im. P.A. Gertsena - filial FGBU «NMIRTs» Minzdrava Rossii, 2017 (in Russian)

2. Adeniran AJ, Zhu Z, Gandhi M, Steward DL, Fidler JP, Giordano TJ, et al. Correlation Between Genetic Alterations and Microscopic Features, Clinical Manifestations, and Prognostic Characteristics of Thyroid Papillary Carcinomas. American Journal of Surgical Pathology. 2006 Feb;30(2):216-22. doi: 10.1097/01.pas.0000176432.73455.1b

3. Agrawal N, Akbani R, Aksoy B Arman, Ally A, Arachchi H, Asa Sylvia L, et al. Integrated Genomic Characterization of Papillary Thyroid Carcinoma. Cell. 2014 Oct;159(3):676-90. doi: 10.1016/j.cell.2014.09.050

4. Al-Salama ZT, Keam SJ. Entrectinib: First Global Approval. Drugs. 2019 Aug 1;79(13):1477-83. doi:10.1007/s40265-019-01177-y

5. Amin MB, Edge SB, American. AJCC cancer staging manual. Switzerland: Springer; 2017.

6. Cahoon EK, Nadyrov EA, Polyanskaya ON, Yauseyenka VV, Veyalkin IV, Yeudachkova TI, et al. Risk of Thyroid Nodules in Residents of Belarus Exposed to Chernobyl Fallout as Children and Adolescents. The Journal of Clinical Endocrinology & Metabolism. 2017 Mar 22;102(7):2207-17 doi:10.1210/jc.2016-3842

7. Castro P, Rebocho AP, Soares RJ, Magalhaes J, Roque L, Trovisco V, et al. PAX8-PPARy Rearrangement Is Frequently Detected in the Follicular Variant of Papillary Thyroid Carcinoma. The Journal of Clinical Endocrinology & Metabolism. 2006 Jan;91(1):213-20. doi:10.1210/jc.2005-1336

8. Cocco E, Scaltriti M, Drilon A. NTRK fusionpositive cancers and TRK inhibitor therapy. Nature Reviews Clinical Oncology. 2018 Oct 17;15(12):731-47. doi:10.1038/s41571-018-0113-0

9. Cox AD, Der CJ. Ras history. Small GTPases. 2010 Jul;1(1):2-27. doi:10.4161/sgtp.1.1.12178

10. Crescenzi A, Fulciniti F, Bongiovanni M, Gio-vanella L, Trimboli P. Detecting N-RAS Q61R Mutated Thyroid Neoplasias by Immunohistochemistry. Endocrine Pathology. 2017 Jan 7;28(1):71-4. doi:10.1007/s12022-016-9466-z

11. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature [Internet]. 2002 Jun;417(6892):949-54. doi:10.1038/nature00766

12. Der CJ, Krontiris TG, Cooper GM. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. Proceedings of the National Academy of Sciences. 1982 Jun 1;79(11):3637-40. doi: 10.1073/pnas.79.11.3637

13. FDA Approves Selpercatinib; Pralsetinib May Soon Follow. Cancer Discovery. 2020 Jun 3;10(7):OF1-1. doi: 10.1158/2159-8290.CD-NB2020-052.

14. Harvey JJ. An Unidentified Virus which causes the Rapid Production of Tumours in Mice. Nature. 1964 Dec;204(4963):1104-5. doi: 10.1038/2041104b0

15. Hall A, Marshall CJ, Spurr NK, Weiss RA. Identification of transforming gene in two human sarcoma cell lines as a new member of the ras gene family located on chromosome 1. Nature. 1983 Jun;303(5916):396-400. doi: 10.1038/303396a0

16. Hsiao SJ, Nikiforov Y. Molecular approaches to thyroid cancer diagnosis. Endocrine Related Cancer. 2014;21(5):T301-T313. doi:10.1530/ERC-14-0166

17. Imaizumi M, Ohishi W, Nakashima E, Sera N, Neriishi K, Yamada M, et al. Association of Radiation Dose With Prevalence of Thyroid Nodules Among Atomic Bomb Survivors Exposed in Childhood (2007-2011). JAMA Internal Medicine. 2015 Feb 1;175(2):228.-36. doi: 10.1001/jamainternmed.2014.6692. Erratum in: JAMA Intern Med. 2020 Jan 1;180(1):167. PMID: 25545696.

18. Kirsten WH, Mayer LA. Morphologic responses to a murine erythroblastosis virus. J Natl Cancer Inst 1967; 39:311-35. doi: 10.1093/jnci/39.2.311

19. Kombak FE, Ozkan N, Ugurlu MU, Kaya H. Brafv600e immunohistochemistry in papillary thyroid carcinomas: relationship between clinical and morphological parameters. Turkish Journal of Pathology. 2019. doi:10.5146/tjpath.2018.01448

20. Landa I, Ibrahimpasic T, Boucai L, Sinha R, Knauf JA, Shah RH, et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. Journal of Clinical Investigation. 2016 Feb 15;126(3):1052-66. doi:10.1172/JCI85271

21. Leeman-Neill RJ, Kelly LM, Liu P, Brenner AV, Little MP, Bogdanova TI, et al. ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer. 2013 Dec 10;120(6):799-807. doi: 10.1002/cncr.28484

22. Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM, et al. Cancer treatment and survivorship statistics, 2019. CA: A Cancer Journal for Clinicians. 2019 Jun 11;69(5): 363385. doi:10.3322/caac.21565

23. Mitro SD, Rozek LS, Vatanasapt P, Suwanrungruang K, Chitapanarux I, Srisukho S, et al. Iodine deficiency and thyroid cancer trends in three regions of Thailand, 1990-2009. Cancer Epidemiology. 2016 Aug;43:92-99. doi:10.1016/j.canep.2016.07.002

24. Mitsutake N, Fukushima T, Matsuse M, Rogouno-vitch T, Saenko V, Uchino S, et al. BRAFV600E mutation is highly prevalent in thyroid carcinomas in the young population in Fukushima: a different oncogenic profile from Chernobyl. Scientific Reports. 2015 Nov 20;5(1):16976. doi: 10.1038/srep16976

25. Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nature Reviews Drug Discovery. 2020 Jun 11;19(8):533-52. doi:10.1038/s41573-020-0068-6

26. Musholt TJ, Staubitz JI, Antonio Camara RJ, Mu-sholt PB, Humberg D, Springer E, et al. Detection of RET rearrangements in papillary thyroid carcinoma using RT-PCR and FISH techniques - A molecular and clinical analysis. European Journal of Surgical Oncology. 2019 Jun;45(6):1018-24. doi: 10.1016/j.ejso.2018.11.009

27. Nechifor-Boila AC, Szasz EA, Descotes F, Berger N, Zahan AE, Loghin A, Cetera§ DM, Borda A. Morphological features predictive for BRAF(V600E) mutation in papillary thyroid microcarcinomas. Rom J Morphol Embryol. 2018;59(3):747-753. PMID: 30534813.

28. Nikiforov YE. RET/PTC rearrangement in thyroid tumors. Endocrine Pathology. 2002;13(1):3-16. doi: 10.1385/ep:13:1:03

29. Park JY, Kim WY, Hwang TS, Lee SS, Kim H, Han HS, et al. BRAF and RAS Mutations in Follicular Variants of Papillary Thyroid Carcinoma. Endocrine Pathology. 2013 Apr 30;24(2):69-76. doi:10.1007/s12022-013-9244-0

30. Ricciuti B, Genova C, Crind L, Libra M, Leonardi GC. Antitumor activity of larotrectinib in tumors harboring NTRK gene fusions: a short review on the current evidence. OncoTargets and Therapy. 2019 Apr;Volume 12:3171-9. doi:10.2147/OTT.S177051

31. Rossi ED, Bizzarro T, Martini M, Capodimonti S, Cenci T, Fadda G, et al. Morphological features that can predict BRAFV600E-mutated carcinoma in paediatric thyroid cytology. Cytopathology. 2016 Jun 3;28(1):55-64. doi:10.1111/cyt.12350

32. Rossi ED, Bizzarro T, Martini M, Capodimonti S, Fadda G, Larocca LM, et al. Morphological parameters able to predictBRAFV600E-mutated malignancies on thyroid fine-needle aspiration cytology: Our institutional experience. Cancer Cy-topathology. 2014 Aug 25;122(12):883-91. doi: 10.1002/cncy.21475

33. Seethala RR, Chiosea SI, Liu CZ, Nikiforova M, Nikiforov YE. Clinical and Morphologic Features of ETV6-NTRK3 Translocated Papillary Thyroid Carcinoma in an Adult Population Without Radiation Exposure. American Journal of Surgical Pathology. 2017 Apr;41(4):446-57. doi:10.1097/PAS.0000000000000814

34. Singarayer R, Mete O, Perrier L, Thabane L, Asa SL, Van Uum S, et al. A Systematic Review and Meta-Analysis of the Diagnostic Performance of BRAF V600E Immunohistochemistry in Thyroid Histopathology. Endocrine Pathology. 2019 Jul 12;30(3):201-18. doi: 10.1007/s12022-019-09585-2.

35. Solomon JP, Linkov I, Rosado A, Mullaney K, Rosen EY, Frosina D, et al. NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls. Modern Pathology. 2019 Aug 2;33(1):38-46. doi: 10.1038/s41379-019-0324-7

36. Zhu Z, Gandhi M, Nikiforova MN, Fischer AH, Nikiforov YE. Molecular Profile and Clinical-Pathologic Features of the Follicular Variant of Papillary Thyroid Carcinoma. American Journal of Clinical Pathology. 2003 Jul;120(1):71-7. doi: 10.1309/nd8d9lajtrctg6qd