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Nuclear Features of Papillary Thyroid Carcinoma (BRAF-Like Tumors), Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (RAS-Like Tumors), and Follicular Adenoma/Follicular Thyroid Carcinoma (RAS-Like Tumors)

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Thyroid FNA Cytology

Abstract

In seminal papers for noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and the fourth edition WHO classification, NIFTP was defined by the following four features: (1) noninvasive, (2) encapsulated, (3) follicular pattern, and (4) papillary thyroid carcinoma-type nuclear features (PTC-N). However, most Asian pathologists have difficulty in diagnosing NIFTP and are often unable to distinguish noninvasive encapsulated classic papillary thyroid carcinoma (PTC) with predominant follicular pattern from NIFTPs. This is because most Asian pathologists accept only those features seen in classic PTC as PTC-N. This was evidenced by some NIFTP cases from Asian series being reported as cases of NIFTP with nodal metastasis and/or BRAFV600E mutation. The nuclear features of NIFTP (papillary-like nuclear features or dysplastic nuclear features of RAS-like tumors) are clearly different from those (florid nuclear features or fully developed nuclear features of BRAF-like tumors) observed in classic PTC, although they are both scored as 3 by the nuclear score guide. PTC-N can be divided into two types: nuclear features seen in classic PTC (true PTC-N in BRAF-like tumors) and those in NIFTP (dysplastic nuclear changes in RAS-like tumors). This difference is emphasized particularly for Asian readers in order to recognize the following delicate nuclear changes seen in RAS-like tumors: (1) mild nuclear enlargement, (2) mild nuclear irregularity, (3) delicate grooves, (4) faintly pale chromatin, and (5) very rare or no nuclear cytoplasmic pseudo-inclusions. This wide definition of PTC-N in Western practice encompasses nuclear features of classic PTC (BRAF-like tumors) and NIFTP (RAS-like tumors) in contrast to the narrow definition in Asian practice, which is observed in classic PTC at the invasive stage.

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References

  1. Lloyd RV, Osamura RY, Klöppel G, Rosai J, editors. WHO classification of tumours of endocrine organs. 4th ed. IARC: Lyon; 2017.

    Google Scholar 

  2. Franssila KO. Is the differentiation between papillary and follicular thyroid carcinoma valid? Cancer. 1973;32:853–64.

    CAS  PubMed  Google Scholar 

  3. Chen KT, Rosai J. Follicular variant of thyroid papillary carcinoma: a clinicopathologic study of 6 cases. Am J Surg Pathol. 1977;1:123–30.

    Google Scholar 

  4. DeLellis RA, Lloyd RV, Heitz PU, Eng C. Tumours of endocrine organs, World Health Organization Classification of tumours; pathology and genetics. Lyon: IARC Press; 2004.

    Google Scholar 

  5. Verkooijen HM, Fioretta G, Pache JC, et al. Diagnostic changes as a reason for the increase in papillary thyroid cancer incidence in Geneva, Switzerland. Cancer Causes Control. 2003;14:13–7.

    PubMed  Google Scholar 

  6. Widder S, Guggisberg K, Khalil M, et al. 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. 2008;144:80–5.

    PubMed  Google Scholar 

  7. Jung CK, Little MP, Lubin J, et al. The increase 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. 2014;99:E276–85.

    CAS  PubMed  Google Scholar 

  8. Cipriani NA, Nagar S, Kaplan SP, et al. Follicular thyroid carcinoma: how have histologic diagnoses changed in the last half-century and what are the prognostic implications? Thyroid. 2015;25:1209–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Ohori NP. FNA cytopathology and molecular test characteristics in the changing landscape of papillary thyroid carcinoma. J Basic Clin Med. 2015;4:103–9.

    Google Scholar 

  10. Hakala T, Kholova I. Changes in classification of follicular thyroid cancers. Thyroid. 2016;26:866.

    PubMed  Google Scholar 

  11. Faquin JA, Wells SA. Biologic and clinical perspectives on thyroid cancer. N Engl J Med. 2016;375:1054–67.

    Google Scholar 

  12. Renshaw AA, Gould EW. Why there is the tendency to “overdiagnose” the follicular variant of papillary thyroid carcinoma. Am J Clin Pathol. 2002;117:19–21.

    PubMed  Google Scholar 

  13. Chan J. Strict criteria should be applied in the diagnosis of encapsulated follicular variant of papillary thyroid carcinoma. Am J Clin Pathol. 2002;117:16–8.

    PubMed  Google Scholar 

  14. Mehrzad R, Nishino M, Connolly J, et al. The relationship between the follicular variant of papillary thyroid cancer and follicular adenomas. Surgery. 2016;159(5):1396–406.

    PubMed  Google Scholar 

  15. Tallini G, Tuttle RM, Ghossein RA. The history of the follicular variant of papillary thyroid carcinoma. J Clin Endocrinol Metab. 2017;102:15–22.

    PubMed  Google Scholar 

  16. Bychkov A, Hirokawa M, Jung CK, et al. Low rate of noninvasive follicular thyroid neoplasm with papillary-like nuclear features in Asian practice. Thyroid. 2017;27:983–4.

    PubMed  Google Scholar 

  17. Bychkov A, Keelawat S, Agarwal S, et al. Impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features on risk of malignancy for the Bethesda categories: a multi-institutional study in five Asian countries. Pathology. 2018;50:411–7.

    PubMed  Google Scholar 

  18. Bychkov A, Jung CK, Liu Z, et al. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features in Asian practice: perspectives for surgical pathology and cytopathology. Endocr Pathol. 2018;29:276–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Jung CK, Kim C. Effect of lowering the diagnostic threshold for noninvasive follicular thyroid neoplasm with papillary-like nuclear features: a single-institution experience in Korea. J Basic Clin Med. 2017;6:26–8.

    Google Scholar 

  20. Liu Z, Zhou G, Nakamura M, Koike E, et al. Encapsulated follicular thyroid tumor with equivocal nuclear changes, so called well-differentiated tumor of uncertain malignant potential: a morphological, immunohistochemical and molecular appraisal. Cancer Sci. 2011;102:288–94.

    CAS  PubMed  Google Scholar 

  21. Seethala RR, Baloch ZW, Barletta JA, et al. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features: a review for pathologists. Mod Pathol. 2018;31:39–55.

    CAS  PubMed  Google Scholar 

  22. Kumagai A, Namba H, Akanov Z, et al. Clinical implications of pre-operative rapid BRAF analysis for papillary thyroid cancer. Endocr J. 2007;54:399–405.

    CAS  PubMed  Google Scholar 

  23. Guan H, Ji M, Bao R, et al. Association of high iodine intake with the T1799A BRAF mutation in papillary thyroid carcinoma. J Clin Endocrinol Metab. 2009;94:1612–7.

    CAS  PubMed  Google Scholar 

  24. Jung CK, Im SY, Kang YJ, et al. Mutational patterns and novel mutations of the BRAF gene in a large cohort of Korean patients with papillary thyroid carcinoma. Thyroid. 2012;22:791–7.

    CAS  PubMed  Google Scholar 

  25. Higuchi M, Hirokawa M, Kanematsu R, et al. Impact of the modification of the diagnostic criteria in the 2017 Bethesda System for Reporting Thyroid Cytopathology: a report of a single institution in Japan. Endocr J. 2018;65(12):1193–8. https://doi.org/10.1507/endocrj.EJ18-0290.

    Article  PubMed  Google Scholar 

  26. Nikiforov YE, Seethala RR, Tallini G, et al. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2016;2:1023–9.

    PubMed  PubMed Central  Google Scholar 

  27. Rosario PW, Mourão GF, Nunes MB, Nunes MS, Calsolari MR. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Endocr Relat Cancer. 2016;23(12):893–7.

    CAS  PubMed  Google Scholar 

  28. Hahn SY, Shin JH, Lim HK, et al. Preoperative differentiation between non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and non-NIFTP. Clin Endocrinol (Oxf). 2017;86:444–50.

    CAS  Google Scholar 

  29. Kwon H, Jeon MJ, Yoon JH, et al. Preoperative clinicopathological characteristics of patients with solitary encapsulated follicular variant of papillary thyroid carcinomas. J Surg Oncol. 2017;116:746–55.

    CAS  PubMed  Google Scholar 

  30. Parente D, Kluijfhout WP, Bongers PJ, et al. Clinical safety of renaming encapsulated follicular variant of papillary thyroid carcinoma: Is NIFTP truly benign? World J Surg. 2018;42:321–6.

    PubMed  Google Scholar 

  31. Kim TH, Lee M, Kwon AY, et al. Molecular genotyping of the non-invasive encapsulated follicular variant of papillary thyroid carcinoma. Histopathology. 2018;72(4):648–61. https://doi.org/10.1111/his.13401.

    PubMed  Google Scholar 

  32. Lee SE, Hwang TS, Choi Y-L, et al. Molecular profiling of papillary thyroid carcinoma in Korea with a high prevalence of BRAFV600E mutation. Thyroid. 2017;27:802–10.

    CAS  PubMed  Google Scholar 

  33. Cho U, Mete O, Kim MH, et al. 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. 2017;30:810–25.

    CAS  PubMed  Google Scholar 

  34. Lloyd RV, Asa SL, LiVolsi VA, et al. The evolving diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Hum Pathol. 2018;74:1–4. https://doi.org/10.1016/j.humpath.2017.12.027.

    Article  PubMed  Google Scholar 

  35. Kakudo K, El-Naggar AK, Hodak SP, et al. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in thyroid tumor classification. Pathol Int. 2018;68:327–33.

    PubMed  Google Scholar 

  36. Alves VA, Kakudo K, VA LV, et al. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): achieving better agreement by refining diagnostic criteria. Clinics. 2018;73:e567.

    Google Scholar 

  37. Kakudo K, Bai Y, Katayama S, et al. Classification of follicular cell tumors of the thyroid gland: analysis involving Japanese patients from one institute. Pathol Int. 2009;59:359–67.

    PubMed  Google Scholar 

  38. Kakudo K, Bai Y, Liu Z, et al. Classification of thyroid follicular cell tumors: with special reference to borderline lesions. Endocr J. 2012;59:1–12.

    PubMed  Google Scholar 

  39. Kakudo K, Bai Y, Liu Z, et al. Encapsulated papillary thyroid carcinoma, follicular variant: a misnomer. Pathol Int. 2012;62:155–60.

    PubMed  Google Scholar 

  40. Kakudo K, Wakasa T, Ohta Y, et al. Borderline and precursor lesions of thyroid carcinomas. J Basic Clin Med. 2015;4:2–7.

    Google Scholar 

  41. Rivera M, Tuttle RM, Patel S, Shaha A, Shah JP, Ghossein RA. Encapsulated papillary thyroid carcinoma: a clinico-pathologic study of 106 cases with emphasis on its morphologic subtypes (histologic growth pattern). Thyroid. 2009;19:119–27.

    PubMed  Google Scholar 

  42. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159:676–90.

    Google Scholar 

  43. Paulson VA, Shivdasani P, Angell TE, et al. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features accounts for more than half of “carcinomas” harboring RAS mutations. Thyroid. 2017;27:506–11.

    CAS  PubMed  Google Scholar 

  44. Strickland KC, Howitt BE, Marqusee E, et al. the impact of noninvasive follicular variant of papillary thyroid carcinoma on rates of malignancy for fine-needle aspiration diagnostic categories. Thyroid. 2015;25:987–92.

    PubMed  Google Scholar 

  45. Krane JF, Alexander EK, Cibas ES, et al. Coming to terms with NIFTP: a provisional approach for cytologists. Cancer Cytopathol. 2016;124:767–72.

    PubMed  Google Scholar 

  46. Faquin WC, Wong LQ, Afrogheh AH, et al. Impact of reclassifying noninvasive follicular variant of papillary thyroid carcinoma on the risk of malignancy in the Bethesda system for reporting thyroid cytopathology. Cancer Cytopathol. 2016;124:181–7.

    PubMed  Google Scholar 

  47. Thompson LD. Ninety-four cases of encapsulated follicular variant of papillary thyroid carcinoma: a name change to non-invasive follicular thyroid neoplasm with papillary-like nuclear features would help prevent overtreatment. Mod Pathol. 2016;29:698–707.

    CAS  PubMed  Google Scholar 

  48. Ibrahim AA, Wu HH. Fine-needle aspiration cytology of noninvasive encapsulated follicular variant of papillary thyroid carcinoma is cytomorphologically distinct from the invasive counterpart. Am J Clim Pathol. 2016;146:373–7.

    Google Scholar 

  49. Canberk S, Gunes P, Onenerk M, et al. New concept of the encapsulated follicular variant of papillary thyroid carcinoma and its impact on the Bethesda system for reporting thyroid cytopathology: a single-institute experience. Acta Cytol. 2016;60:198–204.

    PubMed  Google Scholar 

  50. Saglietti C, Bongiovanni M. The value of cytological examination in diagnosis of noninvasive thyroid neoplasm with papillary-like nuclear features (NIFTP). J Basic Clin Med. 2017;6:57–60.

    Google Scholar 

  51. Ng D, Can NT, Ma ZV, et al. Cytomorphologic features of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): a comparison with infiltrative follicular variant of papillary thyroid carcinoma. J Basic Clin Med. 2017;6:51–6.

    Google Scholar 

  52. Yang GCH, Fried KO, Scognamiglio T. Sonographic and cytologic differences of NIFTP from infiltrative or invasive encapsulated follicular variant of papillary thyroid carcinoma: a review of 179 cases. Diagn Cytopathol. 2017;45:533–41.

    PubMed  Google Scholar 

  53. Satoh S, Yamashita H, Kakudo K. Thyroid cytology in Japan: the Japanese system and experience at Yamashita thyroid hospital. J Pathol Trans Med. 2017;51:548–54.

    Google Scholar 

  54. Ohori NP, Wolfe J, Carty SE, et al. The influence of the noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) resection diagnosis on the false-positive thyroid cytology rate relates to quality assurance thresholds and the application of NIFTP criteria. Cancer Cytopathol. 2017;125:692–700.

    PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Faculty of Medicine, Nara Hospital, Kindai University, Ikoma, Japan

    Kennichi Kakudo

  2. Graduate School of Medicine, Wakayama Medical University, Wakayama, Japan

    Kennichi Kakudo

  3. Department of Pathology, Shandong University School of Basic Medical Sciences, Jinan, Shandong, China

    Zhiyan Liu

  4. Department of Pathology, Shandong University Qilu Hospital, Jinan, Shandong, China

    Zhiyan Liu

  5. Faculty of Medicine, Department of Pathology, Chulalongkorn University, Bangkok, Thailand

    Andrey Bychkov

  6. Department of Pathology, Kameda Medical Center, Kamogawa, Chiba, Japan

    Andrey Bychkov

  7. Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

    Chan Kwon Jung

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  1. Kennichi Kakudo
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  4. Chan Kwon Jung
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Correspondence to Kennichi Kakudo .

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  1. Faculty of Medicine, Nara Hospital, Kindai University, Ikoma, Japan

    Kennichi Kakudo

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Kakudo, K., Liu, Z., Bychkov, A., Jung, C.K. (2019). Nuclear Features of Papillary Thyroid Carcinoma (BRAF-Like Tumors), Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (RAS-Like Tumors), and Follicular Adenoma/Follicular Thyroid Carcinoma (RAS-Like Tumors). In: Kakudo, K. (eds) Thyroid FNA Cytology. Springer, Singapore. https://doi.org/10.1007/978-981-13-1897-9_21

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  • DOI: https://doi.org/10.1007/978-981-13-1897-9_21

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