Molecular Correlates and Nuclear Features of Encapsulated Follicular-Patterned Thyroid Neoplasms

Background Assessing nuclear features is diagnostically challenging in the aspect of thyroid pathology. The aim of this study was to determine whether pathologists could distinguish BRAF-like and RAS-like nuclear features morphologically and identify morphological features to differentiate thyroid tumors with RAS-like mutations from encapsulated papillary thyroid carcinoma (PTC) with predominant follicular growth and BRAFV600E mutation. Methods Representative whole slide images of 16 encapsulated thyroid tumors with predominant follicular growth were reviewed by 12 thyroid pathologists using a web browser-based image viewer. Total nuclear score was calculated from semi-quantitatively scored eight nuclear features. The molecular profile of RAS and BRAF genes was determined by Sanger sequencing. Results Total nuclear score ranging 0 to 24 could differentiate BRAF-like tumors from RAS-like tumors with a cut-off value of score 14. The interobserver agreement was the highest for the assessment of nuclear pseudoinclusions (NPIs) but the lowest for nuclear elongation and sickle-shaped nuclei. NPIs were found in tumors with BRAFV600E mutation, but not in tumors with RAS-like mutations. Total nuclear scores were significantly higher for tumors with BRAFV600E than for those with RAS-like mutations (P<0.001). Conclusion Our results suggest that NPIs and high nuclear scores have diagnostic utility as rule-in markers for differentiating PTC with BRAFV600E mutation from benign or borderline follicular tumors with RAS-like mutations. Relaxation of rigid criteria for nuclear features resulted in an overdiagnosis of PTC. Immunostaining or molecular testing for BRAFV600E mutation is a useful adjunct for cases with high nuclear scores to identify true PTC.

[1]  M. Hirokawa,et al.  Prevalence and diagnostic significance of noninvasive follicular thyroid neoplasm with papillary-like nuclear features among tumors previously diagnosed as follicular adenoma: a single-institutional study in Japan. , 2020, Endocrine journal.

[2]  M. Hirokawa,et al.  Histopathologic Assessment of Capsular Invasion in Follicular Thyroid Neoplasms—an Observer Variation Study , 2020, Endocrine Pathology.

[3]  S. Choden,et al.  VE1 Immunohistochemistry Improves the Limit of Genotyping for Detecting BRAFV600E Mutation in Papillary Thyroid Cancer , 2020, Cancers.

[4]  J. Kopczyński,et al.  Noninvasive follicular thyroid neoplasm with papillary-like nuclear features: a problematic entity , 2020, Endocrine connections.

[5]  S. Selvaggi.  The presence of multinucleated giant cells: Noninvasive follicular thyroid neoplasm with papillary‐like nuclear features vs the follicular variant of papillary thyroid carcinoma , 2019, Diagnostic cytopathology.

[6]  S. Asa,et al.  A Systematic Review and Meta-Analysis of the Diagnostic Performance of BRAF V600E Immunohistochemistry in Thyroid Histopathology , 2019, Endocrine Pathology.

[7]  E. Tirrò,et al.  Molecular Alterations in Thyroid Cancer: From Bench to Clinical Practice , 2019, Genes.

[8]  S. Jung,et al.  Atypical Histiocytoid Cells and Multinucleated Giant Cells in Fine-Needle Aspiration Cytology of the Thyroid Predict Lymph Node Metastasis of Papillary Thyroid Carcinoma , 2019, Cancers.

[9]  M. Hirokawa,et al.  Interobserver and intraobserver variation in the morphological evaluation of noninvasive follicular thyroid neoplasm with papillary‐like nuclear features in Asian practice , 2019, Pathology international.

[10]  V. Cogliano.  International Agency for Research on Cancer (IARC) , 2018, The Grants Register 2019.

[11]  T. Giordano,et al.  Change in Diagnostic Criteria for Noninvasive Follicular Thyroid Neoplasm With Papillarylike Nuclear Features , 2018, JAMA oncology.

[12]  K. Kakudo,et al.  Impact of non-invasive follicular thyroid neoplasm with papillary-like nuclear features on the Bethesda system for reporting thyroid cytopathology: a multi-institutional study in five Asian countries. , 2018, Pathology.

[13]  V. Iyer,et al.  Cytopathology of non‐invasive follicular thyroid neoplasm with papillary‐like nuclear features: A comparative study with similar patterned papillary thyroid carcinoma variants , 2018, Cytopathology : official journal of the British Society for Clinical Cytology.

[14]  M. Papotti,et al.  Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features (NIFTP): Achieving Better Agreement By Refining Diagnostic Criteria , 2018, Clinics.

[15]  C. Jung,et al.  Clinical utility of EZH1 mutations in the diagnosis of follicular-patterned thyroid tumors. , 2018, Human pathology.

[16]  R. Seethala,et al.  An International Interobserver Variability Reporting of the Nuclear Scoring Criteria to Diagnose Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features: a Validation Study , 2018, Endocrine Pathology.

[17]  Zhiyan Liu,et al.  Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features in Asian Practice: Perspectives for Surgical Pathology and Cytopathology , 2018, Endocrine Pathology.

[18]  K. Kakudo,et al.  The Use of Fine-Needle Aspiration (FNA) Cytology in Patients with Thyroid Nodules in Asia: A Brief Overview of Studies from the Working Group of Asian Thyroid FNA Cytology , 2017, Journal of pathology and translational medicine.

[19]  K. Kakudo,et al.  Current Practices of Thyroid Fine-Needle Aspiration in Asia: A Missing Voice , 2017, Journal of pathology and translational medicine.

[20]  BychkovAndrey,et al.  Low Rate of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features in Asian Practice , 2017 .

[21]  F. KraneJeffrey,et al.  Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features Accounts for More Than Half of “Carcinomas” Harboring RAS Mutations , 2017 .

[22]  Ozgur Mete,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-lik , 2017, Modern Pathology.

[23]  N. Lindeman,et al.  Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features Accounts for More Than Half of "Carcinomas" Harboring RAS Mutations. , 2017, Thyroid : official journal of the American Thyroid Association.

[24]  J. Fagin,et al.  Biologic and Clinical Perspectives on Thyroid Cancer. , 2016, The New England journal of medicine.

[25]  A. Tischler,et al.  Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors. , 2016, JAMA oncology.

[26]  L. Larocca,et al.  Morphological parameters able to predict BRAFV600E‐mutated malignancies on thyroid fine‐needle aspiration cytology: Our institutional experience , 2014, Cancer cytopathology.

[27]  Steven J. M. Jones,et al.  Integrated Genomic Characterization of Papillary Thyroid Carcinoma , 2014, Cell.

[28]  P. Waring,et al.  Immunohistochemistry with the anti-BRAF V600E (VE1) antibody: impact of pre-analytical conditions and concordance with DNA sequencing in colorectal and papillary thyroid carcinoma , 2014, Pathology.

[29]  P. Dey,et al.  Intranuclear peudoinclusions: Morphology, pathogenesis, and significance , 2012, Diagnostic cytopathology.

[30]  J. Chan,et al.  Nuclear Inclusions and Pseudoinclusions: Friends or Foes of the Surgical Pathologist? , 2010, International journal of surgical pathology.

[31]  J. Rosai.  The Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: Back to the Drawing Board , 2010, Endocrine pathology.

[32]  M. Evans,et al.  Multinucleated Giant Cells’ Incidence, Immune Markers, and Significance: A Study of 172 Cases of Papillary Thyroid Carcinoma , 2009, Head and neck pathology.

[33]  D. Das.  Intranuclear cytoplasmic inclusions in fine‐needle aspiration smears of papillary thyroid carcinoma: A study of its morphological forms, association with nuclear grooves, and mode of formation , 2005, Diagnostic cytopathology.

[34]  M. Hirokawa,et al.  Observer Variation of Encapsulated Follicular Lesions of the Thyroid Gland , 2002, The American journal of surgical pathology.

[35]  T. Legesse,et al.  Distinguishing non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) from classic and invasive follicular-variant papillary thyroid carcinomas based on cytologic features. , 2019, Journal of the American Society of Cytopathology.

[36]  Zhiyan Liu,et al.  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) , 2019, Thyroid FNA Cytology.