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Thyroid Cytology Bethesda Criteria and Molecular Analysis

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Thyroid Cytology Bethesda Criteria and Molecular Analysis Thyroid Fine-Needle Aspiration Cytology & Molecular Testing Opinions & Criticisms Zubair W. Baloch, MD, PhD Professor of Pathology & Laboratory Medicine UPENN Medical Center, Philadelphia, PA Disclosure • Nothing to disclose Lets Start with Basics Objectives of Thyroid FNA • Recognize specific diagnostic entities • Provide meaningful, management oriented diagnosis • Utilization of ancillary techniques as needed The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) The Bethesda System for Reporting Thyroid Cytopathology: Implied Risk of Malignancy and Recommended Clinical Management Diagnostic Category Risk of Malignancy Usual Management (%) Non-diagnostic or Unsatisfactory Repeat FNA with ultrasound guidance Benign 0-3% Clinical follow-up Atypia of Undetermined Significance or ~ 5-15% Repeat FNA Follicular Lesion of Undetermined Significance (AUS/FLUS) Follicular Neoplasm or Suspicious for a 15-30% Surgical lobectomy Follicular Neoplasm (Specify if Hurthle type or Oncocytic) Suspicious for Malignancy 60-75% Near-total thyroidectomy or surgical lobectomy Malignant 97-99% Near-total thyroidectomy Easy Breezy Cytopathology Diagnosis Not Diagnostically Challenging Excellent Concordance Between Clinical Features, Ultrasound and Pathology Nodular Goiter Colloid: Generally abundant . Follicular cells Variable morphology Oncocytes, Macrophages Degeneration/regeneration: Calcification, stromal proliferation, mitoses Chronic Lymphocytic Thyroiditis Oncocytes Lymphocytes: In the background & infiltrating the cell groups Papillary Thyroid Carcinoma Nuclear features – Major Diagnostic Features Elongation, chromatin clearing, Nuclear membrane irregularities Intranuclear grooves Inclusions Small peripheral nucleoli Not so easy - Head Scratching Everyday Thyroid Cytopathology Intdeterminate Lesions Or Indeterminate Pathologist? The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) The Bethesda System for Reporting Thyroid Cytopathology: Implied Risk of Malignancy and Recommended Clinical Management Diagnostic Category Risk of Malignancy Usual Management (%) Non-diagnostic or Unsatisfactory Repeat FNA with ultrasound guidance Benign 0-3% Clinical follow-up Atypia of Undetermined Significance or ~ 5-15% Repeat FNA Follicular Lesion of Undetermined Significance (AUS/FLUS) Follicular Neoplasm or Suspicious for a 15-30% Surgical lobectomy Follicular Neoplasm (Specify if Hurthle type or Oncocytic) Suspicious for Malignancy 60-75% Near-total thyroidectomy or surgical lobectomy Malignant 97-99% Near-total thyroidectomy Diagnosis Follicular Neoplasm 80% Benign on Surgical Excision Diagnosis Follicular Lesion / Neoplasm The Atypical Category The Dreaded AUS/FLUS 10-15% or more Risk of Malignancy Reasons for AUS/FLUS • History – TFT’s, H/O prior FNA • Ultrasound features – Cystic vs. solid • Operator – sampling • Adequacy • Cytology Preparation • Interpretation • Surgical follow-up – ? Gold standard Questions to Myself? How Can I Find Relevance of My Practice of Cytopathology in a Landscape That Won’t Stop Shifting? Let’s Make Sense of Present & Predict Future In Light of Past The Timing of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) Growing Body of Literature Showing Inconsistencies in Surgical Pathology Diagnosis of Thyroid Cancer Among Experts – Encapsulated Follicular Variant of PTC The Cytology Gold Standard is not so Gold TBSRTC Follow-up Clinicopathologic Studies Showing Over-diagnosis and Over-treatment of Thyroid Carcinoma – PTC. Concept of Low and High Risk Disease TBSRTC TBSRTC Clinical and Radiology Guidelines American & European Thyroid Association American College of Radiology American Society of Radiologist in Ultrasound TBSRTC Molecular Profiling of Thyroid Tumors + Molecular Diagnosis of Thyroid Nodules Diagnostic Tests with High Negative and Positive Predictive Value Mutational Analysis Gene Expression Classifier Next Gene Sequencing Growing Body of Literature Showing Inconsistencies in Surgical Pathology Diagnosis of Thyroid Cancer Among Experts – Encapsulated Follicular Variant The Cytology Gold Standard is not so Gold Follow-up Clinicopathologic Studies Showing Over-diagnosis and Over- treatment of Thyroid Carcinoma – PTC. Concept of Low and High Risk Disease TBSRTC Clinical and Radiology Guidelines American & European Thyroid Association American College of Radiology American Society of Radiologist in Ultrasound Molecular Profiling of Thyroid Tumors Molecular Diagnosis of Thyroid Nodules Diagnostic Tests with high Negative and Positive Predictive Value TBSRTC The Aftermath Literature Influx since 12/2007 • PUBMED -1635 publications mentioning • >20% focused on TBSRTC in title and AUS/FLUS Category abstract content – English Literature Thyroid FNA Bethesda Classification Scheme The Bethesda System for Reporting Thyroid Cytopathology: Implied Risk of Malignancy and Recommended Clinical Management Diagnostic Category Risk of Malignancy Usual Management (%) Non-diagnostic or Unsatisfactory Repeat FNA with ultrasound guidance Benign 0-3% Clinical follow-up Atypia of Undetermined Significance or ~ 5-15% Repeat FNA Follicular Lesion of Undetermined Significance (AUS/FLUS) Follicular Neoplasm or Suspicious for a 15-30% Surgical lobectomy Follicular Neoplasm (Specify if Hurthle type or Oncocytic) Suspicious for Malignancy 60-75% Near-total thyroidectomy or surgical lobectomy Malignant 97-99% Near-total thyroidectomy Thyroid FNA Molecular Testing Helping with the Indeterminate Cases 2003 to Present Mutations, Translocations & Rearrangements Further Insights into Morphology Molecular Markers for Thyroid FNA Specimens • Gene expression (mRNA) • Gene mutations • Circulating TSHR mRNA • miRNAs • Proteomics • Combination of marker types Schematic representation of the Mitogen Activated Protein Kinase)MAPK signalling pathway. Ciampi R , Nikiforov Y E Endocrinology 2007;148:936-941 Papillary Thyroid Carcinoma Mutations in Papillary Carcinoma BRAF V600E 46- 75% RET/PTC N ~75% Papillary CA 15% RAS 15-43% PAX8-PPARγ 37% BRAF V601K Non-Papillary Follicular Patterned Lesions Adenoma vs. Carcinoma Mutations & Translocations in Follicular Carcinoma FA FC ~70% Follicular CA 40% N PAX8-PPARγ 30% FC Non-Papillary Oncocytic Follicular Lesions Adenoma vs. Carcinoma Oncocytic Lesions Kras 12/13 75%, NRAS 61 15%, HRAS 4.5%, GRIM-19, TSHR Mutations (autonomously functioning adenomas) PTEN, P13CA & TP53 TCGA Data: Cell. 2014 What we know now.. • BRAF mutations – Most common V600E – Papillary carcinoma pathway (Classic & Tall cell) – Can occur in Anaplastic Carcinoma • Ras mutations (Nras, Hras, Kras) – Follicular patterned lesions (Foll-Adenoma, FVPTC, Foll-Carcinoma) – Kras Oncocytic follicular lesions – Poorly differentiated carcinoma – Nras (18-55%) Very Low Frequency of Limited Panel of Mutation Markers in Follicular Neoplasm Fast forward to Next Generation Sequencing Next-Generation Sequencing • 5-10 ng of input DNA with successful analysis of 99.6% of samples • Simultaneous parallel sequencing of thousands to millions of short nucleic acid sequences • High sensitivity and quantitative assessment • Large scale analyses required for discovery projects • Targeted panels may be useful for molecular dx of thyroid nodules Next-Generation Sequencing UPMC group--34 primers for amplification of targeted genomic areas Nikiforova J Clin Endocrinol Metab 2013;98:E1852-60 Next-Generation Sequencing UPMC group—WHOLE genome/exome/ transcriptome sequencing in mutation negative 26 PTC and 16 FTC Nikiforov, JCEM ThyroSeq v.2 NGS Mutation Panel (Nikiforova et.al. JCEM 2014 & 2015) 14 genes for mutations; 42 fusion types; 16 genes for expression Gene Mutations Gene Fusions Gene expression (DNA) (RNA) (RNA) NRAS RET RET PGK1 – pan-cell marker HRAS TSHR PPARG KRT7 NTRK1 TG Thyroid KRAS AKT1 NTRK3 TTF1 epithelial cells BRAF TP53 BRAF SLC5A5 ALK PIK3CA GNAS Calcitonin – MTC Other PTEN CTNNB1 PTH – parathyroid TERT EIF1AX KRT20 – metastatic Other Molecular Alterations Detected in Fine-Needle Aspiration Samples Diagnosed as Follicular Neoplasm / Suspicious for Follicular Neoplasmand Associated Cancer Risk No. of Samples Cancer Identified at Negative Because of Low Alteration Positive Unique Diagnostic Events Surgery (Cancer Risk, %) Level Point mutations NRAS 16 13 13 (81) 2 KRAS 6 6 5 (83) 4 HRAS 2 2 2 (100) 0 TERT 4 2 4 (100) 0 TSHR 3 3 1 (33) 1 BRAF V600E 1 1 1 (100) 0 BRAF K601E 1 1 0 (0) 0 TP53 1 0 1 (100) 0 PIK3CA 1 0 1 (100) 0 Gene fusions THADA 5 5 5 (100) 0 PPARG 4 4 4 (100) 0 NTRK3 2 2 2 (100) 0 Abbreviations: BRAF, B-Raf proto-oncogene, serine/threonine kinase; FNAs, fine-needle aspiration samples; HRAS, Harvey rat sarcoma viral oncogene homolog; K601E, lysine to glutamic acid substitution at position 601 in BRAF; KRAS, Kirsten rat sarcoma viral oncogene homolog; NRAS, neuroblastoma RAS viral (v-ras) oncogene homolog; NTRK3, neurotrophic tyrosine kinase, receptor, type 3; PIK3CA, phosphatidylinositol4,5-bisphosphate 3-kinase, catalytic subunit α; PPARG, peroxisome proliferator-activated receptor γ; TERT, telomerase reverse transcriptase; THADA, thyroid adenoma associated; TP53, tumor protein 53; TSHR, thyroid-stimulating hormone receptor; V600E, valine to glutamic acid substitution at position 600 in BRAF. Nikiforova Y, et.al. Cancer 2014; 120:3627-34 Highly accurate diagnosis of cancer in thyroid nodules with follicular neoplasm/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next‐generation sequencing assay Nikiforova Y, et.al. Cancer 2014; 120:3627-34 Gene expression classifier (GEC) accurately identifies
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